Nuclear transport modulators and uses thereof

ABSTRACT

The present invention relates to compounds of formula (I): and pharmaceutically acceptable salts thereof, pharmaceutical compositions comprising the compounds of formula I or their pharmaceutically acceptable salts, and methods of using said compounds, salts and compositions in the treatment of various disorders associated with CRM1 activity.

RELATED APPLICATION

This application is the U.S. National Stage of International ApplicationNo. PCT/US2016/069492, filed Dec. 30, 2016, which designates the U.S.,published in English, and claims the benefit of U.S. ProvisionalApplication No. 62/273,857, filed Dec. 31, 2015. The entire teachings ofthe above applications are incorporated herein by reference.

BACKGROUND OF THE INVENTION

Cells from most major human solid and hematologic malignancies exhibitabnormal cellular localization of a variety of oncogenic proteins, tumorsuppressor proteins, and cell cycle regulators (Cronshaw et al, 2004,Falini et al 2006). For example, certain p53 mutations lead tolocalization in the cytoplasm rather than in the nucleus. This resultsin the loss of normal growth regulation, despite intact tumor suppressorfunction. In other tumors, wild-type p53 is sequestered in the cytoplasmor rapidly degraded, again leading to loss of its suppressor function.Restoration of appropriate nuclear localization of functional p53protein can normalize some properties of neoplastic cells (Cai et al,2008; Hoshino et al 2008; Lain et al 1999a; Lain et al 1999b; Smart etal 1999), can restore sensitivity of cancer cells to DNA damaging agents(Cai et al, 2008), and can lead to regression of established tumors(Sharpless & DePinho 2007, Xue et al, 2007). Similar data have beenobtained for other tumor suppressor proteins such as forkhead (Turnerand Sullivan 2008) and c-Abl (Vignari and Wang 2001). In addition,abnormal localization of several tumor suppressor and growth regulatoryproteins may be involved in the pathogenesis of autoimmune diseases(Davis 2007, Nakahara 2009). CRM1 inhibition may provide particularlyinteresting utility in familial cancer syndromes (e.g., Li-FraumeniSyndrome due to loss of one p53 allele, BRCA1 or 2 cancer syndromes),where specific tumor suppressor proteins (TSP) are deleted ordysfunctional and where increasing TSP levels by systemic (or local)administration of CRM1 inhibitors could help restore normal tumorsuppressor function.

Specific proteins and RNAs are carried into and out of the nucleus byspecialized transport molecules, which are classified as importins ifthey transport molecules into the nucleus, and exportins if theytransport molecules out of the nucleus (Terry et al, 2007; Sorokin et al2007). Proteins that are transported into or out of the nucleus containnuclear import/localization (NLS) or export (NES) sequences that allowthem to interact with the relevant transporters. Chromosomal RegionMaintenance 1 (CRM1), which is also called exportin-1 or Xpo1, is amajor exportin.

Overexpression of CRM1 has been reported in several tumors, includinghuman ovarian cancer (Noske et al, 2008), cervical cancer (van der Wattet al, 2009), pancreatic cancer (Huang et al, 2009), hepatocellularcarcinoma (Pascale et al, 2005) and osteosarcoma (Yao et al, 2009) andis independently correlated with poor clinical outcomes in these tumortypes.

Inhibition of CRM1 blocks the exodus of tumor suppressor proteins and/orgrowth regulators such as p53, c-Abl, p21, p27, pRB, BRCA1, IkB, ICp27,E2F4, KLF5, YAP1, ZAP, KLF5, HDAC4, HDAC5 or forkhead proteins (e.g.FOXO3a) from the nucleus that are associated with gene expression, cellproliferation, angiogenesis and epigenetics. CRM1 inhibitors have beenshown to induce apoptosis in cancer cells even in the presence ofactivating oncogenic or growth stimulating signals, while sparing normal(untransformed) cells. Most studies of CRM1 inhibition have utilized thenatural product CRM1 inhibitor Leptomycin B (LMB). LMB itself is highlytoxic to neoplastic cells, but poorly tolerated with markedgastrointestinal toxicity in animals (Roberts et al, 1986) and humans(Newlands et al, 1996). Derivatization of LMB to improve drug-likeproperties leads to compounds that retain antitumor activity and arebetter tolerated in animal tumor models (Yang et al, 2007, Yang et al,2008, Mutka et al, 2009). Therefore, nuclear export inhibitors couldhave beneficial effects in neoplastic and other proliferative disorders.To date, however, small-molecule, drug-like CRM1 inhibitors for use invitro and in vivo are uncommon.

In addition to tumor suppressor proteins, CRM1 also exports several keyproteins that are involved in many inflammatory processes. These includeIkB, NF-kB, Cox-2, RXRα, Commd1, HIF1, HMGB1, FOXO, FOXP and others. Thenuclear factor kappa B (NF-kB/rel) family of transcriptional activators,named for the discovery that it drives immunoglobulin kappa geneexpression, regulate the mRNA expression of variety of genes involved ininflammation, proliferation, immunity and cell survival. Under basalconditions, a protein inhibitor of NF-kB, called IkB, binds to NF-kB inthe nucleus and the complex IkB-NF-kB renders the NF-kB transcriptionalfunction inactive. In response to inflammatory stimuli, IkB dissociatesfrom the IkB-NF-kB complex, which releases NF-kB and unmasks its potenttranscriptional activity. Many signals that activate NF-kB do so bytargeting IkB for proteolysis (Phosphorylation of IkB renders it“marked” for ubiquitination and then proteolysis). The nuclearIkBa-NF-kB complex can be exported to the cytoplasm by CRM1 where itdissociates and NF-kB can be reactivated. Ubiquitinated IkB may alsodissociate from the NF-kB complex, restoring NF-kB transcriptionalactivity. Inhibition of CRM1 induced export in human neutrophils andmacrophage like cells (U937) by LMB not only results in accumulation oftranscriptionally inactive, nuclear IkBa-NF-kB complex but also preventsthe initial activation of NF-kB even upon cell stimulation (Ghosh 2008,Huang 2000). In a different study, treatment with LMB inhibited IL-1βinduced NF-kB DNA binding (the first step in NF-kB transcriptionalactivation), IL-8 expression and intercellular adhesion moleculeexpression in pulmonary microvascular endothelial cells (Walsh 2008).COMMD1 is another nuclear inhibitor of both NF-kB and hypoxia-induciblefactor 1 (HIF1) transcriptional activity. Blocking the nuclear export ofCOMMD1 by inhibiting CRM1 results in increased inhibition of NF-kB andHIF1 transcriptional activity (Muller 2009).

CRM1 also mediates Retinoid X receptor α (RXRα) transport. RXRα ishighly expressed in the liver and plays a central role in regulatingbile acid, cholesterol, fatty acid, steroid and xenobiotic metabolismand homeostasis. During liver inflammation, nuclear RXRα levels aresignificantly reduced, mainly due to inflammation-mediated nuclearexport of RXRα by CRM1. Lep B is able to prevent IL-10 inducedcytoplasmic increase in RXRα levels in human liver derived cells(Zimmerman 2006).

The role of CRM1-mediated nuclear export in NF-kB, HIF-1 and RXRαsignalling suggests that blocking nuclear export can be potentiallybeneficial in many inflammatory processes across multiple tissues andorgans including the vasculature (vasculitis, arteritis, polymyalgiarheumatic, atherosclerosis), dermatologic (see above), rheumatologic(rheumatoid and related arthritis, psoriatic arthritis,spondyloarthropathies, crystal arthropathies, systemic lupuserythematosus, mixed connective tissue disease, myositis syndromes,dermatomyositis, inclusion body myositis, undifferentiated connectivetissue disease, Sjogren's syndrome, scleroderma and overlap syndromes,etc.).

CRM1 Inhibition affects gene expression by inhibiting/activating aseries of transcription factors like ICp27, E2F4, KLF5, YAP1, ZAP

CRM1 inhibition has potential therapeutic effects across manydermatologic syndromes including inflammatory dermatoses (atopy,allergic dermatitis, chemical dermatitis, psoriasis), sun-damage(Ultraviolet/UV damage), and infections. CRM1 inhibition, best studiedwith LMB, showed minimal effects on normal keratinocytes, and exertedanti-inflammatory activity on keratinocytes subjected to UV, TNFa, orother inflammatory stimuli (Kobayashi & Shinkai 2005, Kannan & Jaiswal2006). CRM1 inhibition also upregulates NRF2 (nuclear factorerythroid-related factor 2) activity, which protects keratinocytes(Schafer et al, 2010, Kannan & Jaiswal 2006) and other cell types (Wanget al, 2009) from oxidative damage. LMB induces apoptosis inkeratinocytes infected with oncogenic human papillomavirus (HPV) strainssuch as HPV16, but not in uninfected keratinocytes (Jolly et al, 2009).

CRM1 also mediates the transport of key neuroprotectant proteins thatmay be useful in neurodegenerative diseases including Parkinson'sDisease (PD), Alzheimer's Disease, and Amyotrophic Lateral Sclerosis.For example, (1) forcing nuclear retention of key neuroprotectiveregulators such as NRF2 (Wang 2009), FOXA2 (Kittappa et al, 2007),parking in neuronal cells and/or by (2) inhibiting NFκB transcriptionalactivity by sequestering IκB to the nucleus in glial cells, CRM1inhibition could slow or prevent neuronal cell death found in thesedisorders. There is also evidence linking abnormal glial cellproliferation to abnormalities in CRM1 levels or CRM1 function (Shen2008).

Intact nuclear export, primarily mediated through CRM1, is also requiredfor the intact maturation of many viruses. Viruses where nuclear export,and/or CRM1 itself, has been implicated in their lifecycle include humanimmunodeficiency virus (HIV), adenovirus, simian retrovirus type 1,Borna disease virus, influenza (usual strains as well as H1N1 and avianH5N1 strains), hepatitis B (HBV) and C (HCV) viruses, humanpapillomavirus (HPV), respiratory syncytial virus (RSV), Dungee, SevereAcute Respiratory Syndrome coronavirus, yellow fever virus, West NileVirus, herpes simplex virus (HSV), cytomegalovirus (CMV), and Merkelcell polyomavirus (MCV). (Bhuvanakantham 2010, Cohen 2010, Whittaker1998). It is anticipated that additional viral infections reliant onintact nuclear export will be uncovered in the near future.

The HIV-1 Rev protein, which traffics through nucleolus and shuttlesbetween the nucleus and cytoplasm, facilitates export of unspliced andsingly spliced HIV transcripts containing Rev Response Elements (RRE)RNA by the CRM1 export pathway. Inhibition of Rev-mediated RNA transportusing CRM1 inhibitors such as LepB or PKF050-638 can arrest the HIV-1transcriptional process, inhibit the production of new HIV-1 virions,and thereby reduce HIV-1 levels (Pollard 1998, Daelemans 2002).

Dengue virus (DENV) is the causative agent of the common arthropod-borneviral disease, dengue fever (DF), and its more severe and potentiallydeadly dengue hemorrhagic fever (DHF). DHF appears to be the result ofan over exuberant inflammatory response to DENV. NS5 is the largest andmost conserved protein of DENV. CRM1 regulates the transport of NS5 fromthe nucleus to the cytoplasm, where most of the NS5 functions aremediated. Inhibition of CRM1 mediated export of NS5 results in alteredkinetics of virus production and reduces induction of the inflammatorychemokine interleukin-8 (IL-8), presenting a new avenue for thetreatment of diseases caused by DENV and other medically importantflaviviruses including Hepatitis C virus (Rawlinson 2009).

Other virus-encoded RNA-binding proteins that use CRM1 to exit thenucleus include the HSV type 1 tegument protein (VP13/14, or hUL47),human CMV protein pp65, the SARS Coronavirus ORF 3b Protein, and the RSVmatrix (M) protein (Williams 2008, Sanchez 2007, Freundt 2009, Ghildyal2009).

Interestingly, many of these viruses are associated with specific typesof human cancer including hepatocellular carcinoma (HCC) due to chronicHBV or HCV infection, cervical cancer due to HPV, and Merkel cellcarcinoma associated with MCV. CRM1 inhibitors could therefore havebeneficial effects on both the viral infectious process as well as onthe process of neoplastic transformation due to these viruses.

CRM1 controls the nuclear localization and therefore activity ofmultiple DNA metabolizing enzymes including histone deacetylases (HDAC),histone acetyltransferases (HAT), and histone methyltransferases (HMT).Suppression of cardiomyocyte hypertrophy with irreversible CRM1inhibitors has been demonstrated and is believed to be linked to nuclearretention (and activation) of HDAC 5, an enzyme known to suppress ahypertrophic genetic program (Monovich et al, 2009). Thus, CRM1inhibition may have beneficial effects in hypertrophic syndromes,including certain forms of congestive heart failure and hypertrophiccardiomyopathies.

CRM1 has also been linked to other disorders. Leber's disorder, ahereditary disorder characterized by degeneration of retinal ganglioncells and visual loss, is associated with inaction of the CRM1 switch(Gupta N 2008). There is also evidence linking neurodegenerativedisorders to abnormalities in nuclear transport.

In view of the above, the discovery of compounds that modulate nucleartransport is desirable.

SUMMARY OF THE INVENTION

The present invention relates to compounds, and pharmaceuticallyacceptable salts thereof, useful as nuclear transport modulators;pharmaceutically acceptable compositions comprising compounds of thepresent invention or their pharmaceutically acceptable salts; andmethods of using said compounds, salts and compositions in the treatmentof various disorders.

The compounds of the invention have general formula I:

wherein each variable is as defined and described herein.

Compounds of the present invention and pharmaceutically acceptable saltsand compositions thereof are useful for treating a variety of diseases,disorders or conditions associated with abnormal cellular responsestriggered by improper nuclear transport. Therefore, one embodiment ofthe invention is use of a compound of the invention, or apharmaceutically acceptable salt thereof, for treating a variety ofdiseases, disorders or conditions associated with abnormal cellularresponses triggered by improper nuclear transport. Another embodiment ofthe invention is a method for treating a variety of diseases, disordersor conditions associated with CRM1 activity in a subject in needthereof, the method comprising administering to the subject in needthereof a therapeutically effective amount of a compound the invention,or a pharmaceutically acceptable salt or composition thereof. Suchdiseases, disorders, or conditions include those described herein.

Compounds of the invention, and pharmaceutically acceptable saltsthereof, are also useful in the manufacture of a medicament for thetreatment of a variety of diseases, disorders or conditions associatedwith abnormal cellular responses triggered by improper nucleartransport. Such diseases, disorders, or conditions include thosedescribed herein.

Compounds provided by this invention are also useful for the study ofnuclear transport modulation in biological and pathological phenomena;the study of intracellular signal transduction pathways mediated by, forexample, kinases; and the comparative evaluation of new nucleartransport modulators.

DETAILED DESCRIPTION OF THE INVENTION

Compounds of the Invention

A first embodiment of the invention is a compound of structural formulaI:

or a pharmaceutically acceptable salt thereof, wherein:

-   -   X is —C(H)— or —N—;    -   or a pharmaceutically acceptable salt thereof, wherein:        -   each R¹, if present, is independently selected from —CF₃,            —CN, halo, —OH, C₁-C₃ alkyl, C₃-C₆ cycloalkyl, 3-18-membered            heterocyclyl, —NH₂, halo-C₁-C₃ alkyl, —NO₂, —NH(C₁-C₃            alkyl), —C(O)O—(C₁-C₆ alkyl), —N(C₁-C₃ alkyl)(C₁-C₃ alkyl),            —C(O)OH, —C(O)—(C₁-C₃ alkyl), —O—(C₁-C₃ alkyl), —O—(C₁-C₃            haloalkyl), and —S—(C₁-C₃ alkyl);        -   R² is a 6-18-membered aryl or a 5-18-membered heteroaryl            substituted with one or more substituents, wherein at least            one substituent is —S(O)₁₋₂—R⁸ or N(H)S(O)₁₋₂—R⁸;    -   R^(b) is selected from —C(O)—O—R³, —C(O)—N(R⁵)(R⁶),        —C(O)—N(R⁷)—N(R⁵)(R⁶), —C(O)—N(R⁷)—N(R⁷)—C(O)—R⁴ and        —C(O)—N(R⁷)—N(R⁷)—S(O)₁₋₂—R⁴; wherein:    -   R³ is selected from hydrogen, —C₁-C₄ alkyl, —C₂-C₄ alkenyl,        —C₂-C₄ alkynyl, C₃-C₁₈ carbocyclyl, C₆-C₁₈ aryl, 3-18-member        heterocyclyl and 5-18-member heteroaryl;    -   R⁴ is selected from —N(H)(C₃-C₆ cycloalkyl), —N(C₁-C₄        alkyl)(C₃-C₆ cycloalkyl), —C₁-C₆ alkyl, —(C₀-C₄ alkylene)-C₃-C₁₈        carbocyclyl, —(C₀-C₄ alkylene)-3-18-member heterocyclyl, —(C₀-C₄        alkylene)-C₆-C₁₈ aryl, and —(C₀-C₄ alkylene)-5-18-member        heteroaryl;    -   R⁵ and R⁶ are each independently selected from hydrogen, —C₁-C₄        alkyl, —C₂-C₄ alkenyl, —C₂-C₄ alkynyl, C₃-C₁₈ carbocyclyl,        C₆-C₁₈ aryl, 3-18-member heterocyclyl and 5-18-member        heteroaryl; or    -   R⁵ and R⁶ are taken together with the nitrogen atom to which        they are commonly attached to form a 3-18-member heterocyclyl or        5-18-member heteroaryl; and    -   each R⁷ is independently hydrogen or —C₁-C₄ alkyl;    -   R⁸ is selected from —N(R⁹)—R¹⁰, (C₁-C₄)alkyl, (C₁-C₄)haloalkyl,        —(C₀-C₄ alkylene)-C₃-C₁₈ carbocyclyl, and —(C₀-C₄        alkylene)-3-18-member heterocyclyl;    -   R⁹ is hydrogen or —C₁-C₄ alkyl;    -   R¹⁰ is selected from —(C₁-C₄)alkyl, —(C₁-C₄)haloalkyl, —(C₀-C₄        alkylene)-C₃-C₁₈ carbocyclyl and —(C₀-C₄ alkylene)-3-18-member        heterocyclyl; or    -   R⁹ and R¹⁰ are taken together with the nitrogen atom to which        they are commonly attached to form a 4-7-membered heterocyclyl;    -   n is 0, 1, 2, 3, 4 or 5, wherein:    -   unless otherwise designated, each alkyl, alkenyl, alkynyl,        alkylene, carbocyclyl, aryl, cycloalkyl, heterocyclyl and        heteroaryl is optionally and independently substituted.

In a first aspect of the first embodiment, X is N. The values for theremaining variables are as described in the first embodiment.

In a second aspect of the first embodiment, —C(H). The values for theremaining variables are as described in the first embodiment.

In a third aspect of the first embodiment, R^(b) is selected from—C(O)—OH, —C(O)—NH₂, —C(O)—N(R⁷)—N(R⁵)(R⁶), —C(O)—N(R⁷)—N(R⁷)—C(O)—R⁴and —C(O)—N(R⁷)—N(R⁷)—S(O)₁₋₂—R⁴. The values for the remaining variablesare as described in the first embodiment or the first and second aspectsthereof.

In a fourth aspect of the first embodiment, R^(b) is selected from—C(O)—OH; —C(O)—NH₂; —C(O)—NH—NH(R⁶), wherein R⁶ is an optionallysubstituted heteroaryl;

—C(O)—NH—NH—C(O)—R⁴; and —C(O)—NH—NH—S(O)₁₋₂—R⁴ wherein R⁴ is selectedfrom optionally substituted —N(H)(C₃-C₆ cycloalkyl), —N(C₁-C₄alkyl)(C₃-C₆ cycloalkyl), —C₁-C₆ alkyl, —(C₀-C₄ alkylene)-3-18-memberheterocyclyl and —(C₀-C₄ alkylene)-5-18-member heteroaryl. The valuesfor the remaining variables are as described in the first embodiment orthe first and second aspects thereof.

In a fifth aspect, R^(b) is —C(O)NH₂. The values for the remainingvariables are as described in the first embodiment or the first andsecond aspects thereof.

In a sixth aspect, R² is a 6-12-membered aryl or a 5-12-memberedheteroaryl. The values for the remaining variables are as described inthe first embodiment or the first through fifth aspects thereof.

In a seventh aspect of the first embodiment, R² is phenyl. The valuesfor the remaining variables are as described in the first embodiment orthe first through fifth aspects thereof.

In a eighth aspect of the first embodiment, R² is a 5-6-memberedheteroaryl. The values for the remaining variables are as described inthe first embodiment or the first through fifth aspects thereof.

In an ninth aspect of the first embodiment, R² is a 5-memberedheteroaryl. The values for the remaining variables are as described inthe first embodiment or the first through fifth aspects thereof.

In a tenth aspect of the first embodiment, R² is pyrrolyl, furanyl,thiophenyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl,isoxazolyl, triazolyl, thiadiazolyl, or oxadiazolyl. The values for theremaining variables are as described in the first embodiment or thefirst through fifth aspects thereof.

In an eleventh aspect of the first embodiment, R² is a 6-memberedheteroaryl. The values for the remaining variables are as described inthe first embodiment or the first through fifth aspects thereof.

In a twelfth aspect of the first embodiment, R² is pyridinyl,pyrimidinyl, pyrazinyl, pyridazinyl or triazinyl. The values for theremaining variables are as described in the first embodiment or thefirst through fifth aspects thereof.

In a thirteenth aspect of the first embodiment, the at least onesubstituent of R² is —S(O)₁₋₂—R⁸. The values for the remaining variablesare as described in the first embodiment or the first through twelfthaspects thereof.

In a fourteenth aspect of the first embodiment, R⁸ is —N(R⁹)—R¹⁰. Thevalues for the remaining variables are as described in the firstembodiment or the first through thirteenth aspects thereof.

In a fifteenth aspect of the first embodiment, R⁸ is —N(Me)-Me or —N(H)—cyclopropyl. The values for the remaining variables are as described inthe first embodiment or the first through fourteenth aspects thereof.

In a sixteenth aspect of the first embodiment, R⁸ is —(C₁-C₄)alkyl,—(C₁-C₄)haloalkyl, —(C₀-C₄ alkylene) C₃-C₁₈ carbocyclyl, or —(C₀-C₄alkylene) 3-18-member heterocyclyl wherein each alkyl, carbocyclyl andheterocyclyl is optionally substituted. The values for the remainingvariables are as described in the first embodiment or the first throughthirteenth aspects thereof.

In a seventeenth aspect of the first embodiment, R⁸ is optionallysubstituted (C₀-C₄ alkylene) C₃-C₁₈ carbocyclyl. The values for theremaining variables are as described in the first embodiment or thefirst through thirteenth or sixteenth aspects thereof.

In an eighteenth aspect of the first embodiment, R⁸ is optionallysubstituted (C₃-C₆)—C₃-C₁₈ carbocyclcyl. The values for the remainingvariables are as described in the first embodiment or the first throughthirteenth, sixteenth or seventeenth aspects thereof.

In a nineteenth aspect of the first embodiment, R⁸ is optionallysubstituted cyclopropyl. The values for the remaining variables are asdescribed in the first embodiment or the first through thirteenth orsixteenth through eighteenth aspects thereof.

In a twentieth aspect of the first embodiment, R⁸ is optionallysubstituted 3-12-membered heterocyclyl. The values for the remainingvariables are as described in the first embodiment or the first throughthirteenth aspects thereof.

In a twenty-first aspect of the first embodiment, R⁸ is pyrrolyl,furanyl, thiophenyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl,oxazolyl, isoxazolyl, triazolyl, thiadiazolyl, or oxadiazolyl; andwherein R⁸ is optionally substituted. The values for the remainingvariables are as described in the first embodiment or the first throughthirteenth or twentieth aspects thereof.

In a twenty-second aspect of the first embodiment, R⁸ is optionallysubstituted with 1, 2 or 3 substituents independently selected fromhalo, (C₁-C₄)alkyl, halo-(C₁-C₄)alkyl, (C₁-C₄)alkoxy, (C₁-C₄)thioalkoxy,hydroxyl, amino, (C₁-C₄)alkylamino, (C₁-C₄)dialkylamino, sulfhydryl,cyano, phenyl and a 5-6-membered heteroaryl. The values for theremaining variables are as described in the first embodiment or thefirst through twenty-first aspects thereof.

In a twenty-third aspect of the first embodiment, R⁸ is substituted with1, 2 or 3 substituents independently selected from halo, hydroxyl,halo(C₁-C₃)alkyl, (C₁-C₃)alkyl and (C₁-C₃)alkoxy. The values for theremaining variables are as described in the first embodiment or thefirst through twenty-first aspects thereof.

In a twenty-fourth aspect of the first embodiment, R⁸ is optionallysubstituted with 1, 2 or 3 substituents independently selected fromfluoro, chloro, (C₁-C₄)alkyl, —CF₃, amino and cyano. The values for theremaining variables are as described in the first embodiment or thefirst through twenty-first aspects thereof.

In a twenty-fifth aspect of the first embodiment, R⁸ is selected from:

The values for the remaining variables are as described in the firstembodiment or the first through thirteenth aspects thereof.

In a twenty-sixth aspect of the first embodiment, n is 0, 1 or 2. Thevalues for the remaining variable are as described in the firstembodiment or the first through twenty-sixth aspects thereof.

In a twenty-seventh aspect of the first embodiment, n is 1 or 2 and eachR¹ is independently selected from halo, (C₁-C₄)alkyl, (C₁-C₄)haloalkyland —O—(C₁-C₄)alkyl. The values for the remaining variable are asdescribed in the first embodiment or the first through twenty-sixthaspects thereof.

A second embodiment of the invention is a compound represented bystructural formula III:

or a pharmaceutically acceptable salt thereof. The values for theremaining variable are as described in the first embodiment or the thirdthrough twenty-fifth aspects thereof.

A third embodiment of the invention is a compound represented by thefollowing structural formula:

or a pharmaceutically acceptable salt thereof, wherein:

-   -   R^(1a) and R^(1b) are independently selected from —CF₃, —CN,        halo, —OH, (C₁-C₃)alkyl, (C₃-C₆)cycloalkyl, 3-12-membered        heterocyclyl, halo-(C₁-C₃)alkyl, —NH₂, —NO₂, —NH(C₁-C₃ alkyl),        —N(C₁-C₃ alkyl)(C₁-C₃ alkyl), —C(O)OH, —C(O)O—(C₁-C₆ alkyl),        —C(O)—(C₁-C₃ alkyl), —O—(C₁-C₃ alkyl), —O—(C₁-C₃ haloalkyl), and        —S—(C₁-C₃ alkyl); and m is 0 or 1. The values for the remaining        variable are as described in the first embodiment and the first        through twenty-fifth aspects thereof.

In a first aspect of the third embodiment, R^(1a) is halo or(C₁-C₃)haloalkyl. The values for the remaining variable are as describedin the first embodiment and the first through twenty-fifth aspectsthereof.

In a second aspect of the third embodiment, R^(1a) is (C₁-C₃)haloalkyl.The values for the remaining variable are as described in the firstembodiment, the first through twenty-fifth aspects thereof or the thirdembodiment.

In a third aspect of the third embodiment, R^(1b) is (C₁-C₃)haloalkyl or—O(C₁-C₃)alkyl. The values for the remaining variable are as describedin the first embodiment, the first through twenty-fifth aspects thereof,the third embodiment or the first or second aspect of the thirdembodiment.

In a fourth aspect of the third embodiment, R^(1b) is (C₁-C₃)haloalkyl.The values for the remaining variable are as described in the firstembodiment, the first through twenty-fifth aspects thereof, the thirdembodiment or the first or second aspect of the third embodiment.

In a fifth aspect of the third embodiment, R^(1a) is —CF₃ and R^(1b) is—CF₃. The values for the remaining variable are as described in thefirst embodiment, the first through twenty-fifth aspects thereof or thethird embodiment.

A fourth embodiment of the invention is a compound represented by anyone of the following structural formulas:

or a pharmaceutically acceptable salt thereof.

Compounds and Definitions

Compounds of this invention include those described generally above, andare further illustrated by the classes, subclasses, and speciesdisclosed herein. As used herein, the following definitions shall applyunless otherwise indicated. For purposes of this invention, the chemicalelements are identified in accordance with the Periodic Table of theElements, CAS version, Handbook of Chemistry and Physics, 75^(th) Ed.Additionally, general principles of organic chemistry are described in“Organic Chemistry”, Thomas Sorrell, University Science Books,Sausalito: 1999, and “March's Advanced Organic Chemistry”, 5^(th) Ed.,Ed.: Smith, M. B. and March, J., John Wiley & Sons, New York: 2001, theentire contents of which are hereby incorporated by reference.

Unless specified otherwise within this specification, the nomenclatureused in this specification generally follows the examples and rulesstated in Nomenclature of Organic Chemistry, Sections A, B, C, D, E, F,and H, Pergamon Press, Oxford, 1979, which is incorporated by referenceherein for its exemplary chemical structure names and rules on namingchemical structures. Optionally, a name of a compound may be generatedusing a chemical naming program: ACD/ChemSketch, Version 5.09/September2001, Advanced Chemistry Development, Inc., Toronto, Canada.

Compounds of the present invention may have asymmetric centers, chiralaxes, and chiral planes (e.g., as described in: E. L. Eliel and S. H.Wilen, Stereo-chemistry of Carbon Compounds, John Wiley & Sons, NewYork, 1994, pages 1119-1190), and occur as racemates, racemic mixtures,and as individual diastereomers or enantiomers, with all possibleisomers and mixtures thereof, including optical isomers, being includedin the present invention.

The term “aliphatic” or “aliphatic group,” as used herein, denotes amonovalent hydrocarbon radical that is straight-chain (i.e.,unbranched), branched, or cyclic (including fused, bridged, andspiro-fused polycyclic). An aliphatic group can be saturated or cancontain one or more units of unsaturation, but is not aromatic. Unlessotherwise specified, aliphatic groups contain 1-20 carbon atoms.However, in some embodiments, an aliphatic group contains 1-12, 1-10,2-8 or 1-6 carbon atoms. In some embodiments, aliphatic groups contain1-4 carbon atoms and, in yet other embodiments, aliphatic groups contain1-3 carbon atoms. Suitable aliphatic groups include, but are not limitedto, linear or branched, alkyl, alkenyl, and alkynyl groups, and hybridsthereof, such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or(cycloalkyl)alkenyl. Unless otherwise specified, aliphatic groups areoptionally substituted.

The term “alkyl,” as used herein, pertains to a monovalent moietyobtained by removing a hydrogen atom from a carbon atom of a hydrocarboncompound having a given number of carbon atoms. The alkyl can be alinear or branched alkyl of one to twenty carbon atoms (e.g., 1-6 carbonatoms, 1-4 carbon atoms, 1-3 carbon atoms). Examples of alkyl include,but are not limited to, methyl, ethyl, 1-propyl, 2-propyl, 1-butyl,2-methyl-1-propyl, —CH₂CH(CH₃)₂), 2-butyl, 2-methyl-2-propyl, 1-pentyl,2-pentyl 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl,2-methyl-1-butyl, 1-hexyl), 2-hexyl, 3-hexyl, 2-methyl-2-pentyl,3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl,2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, 3,3-dimethyl-2-butyl, 1-heptyl,1-octyl, and the like. Typically, the alkyl is a C₁-C₁₂ alkyl,preferably C₁-C₆. As such, “C₁-C₆ alkyl” means a straight or branchedsaturated monovalent hydrocarbon radical having from one to six carbonatoms (e.g., 1, 2, 3, 4, 5 or 6). Examples of alkyl groups include, butare not limited to, methyl, ethyl, propyl, isopropyl, and t-butyl.Unless otherwise specified, alkyl groups are optionally substituted

The term “alkoxy,” as used herein, means an “alkyl-O—” group, whereinalkyl is defined above. Examples of alkoxy include methoxy and ethoxy.

“Alkenyl” refers to linear or branched-chain monovalent hydrocarbonradical of the specified number of carbons. For example, alkenyl canhave two to twenty carbon atoms (e.g., 2-10 or 2-4) with at least onesite of unsaturation, i.e., a carbon-carbon, double bond. The alkenylradical includes radicals having “cis” and “trans” orientations, oralternatively, “E” and “Z” orientations. Examples include, but are notlimited to, vinyl (—CH═CH₂), allyl (—CH₂CH═CH₂), and the like. If analkenyl group includes more than one carbon-carbon double bond, eachcarbon-carbon double bond is independently a cis or trans double bond,or a mixture thereof. Unless otherwise specified, alkenyl groups areoptionally substituted with one or more substituents.

“Alkynyl” refers to a linear or branched monovalent hydrocarbon radicalof the specified number of carbons. For example, alkynyl can have two totwenty carbon atoms (e.g., 2-4 with at least one site of unsaturation,i.e., a carbon-carbon, triple bond. Examples include, but are notlimited to, ethynyl, propynyl, 1-butynyl, 2-butynyl, 1-pentynyl,2-pentynyl, 3-pentynyl, hexynyl, and the like. Preferably, the alkynylhas two to ten carbon atoms. More preferably, the alkynyl has two tofour carbon atoms. Unless otherwise specified, alkynyl groups areoptionally substituted with one or more substituents.

As used herein, the term “alkylene” refers to an alkyl group having thespecified number of carbons, for example from 2 to 12 carbon atoms, thatcontains two points of attachment to the rest of the compound on itslongest carbon chain. Non-limiting examples of alkylene groups includemethylene —(CH₂)—, ethylene —(CH₂CH₂)—, n-propylene —(CH₂CH₂CH₂)—,isopropylene —(CH₂CH(CH₃))—, and the like. Alkylene groups may beoptionally substituted with one or more substituents.

The term “amino,” as used herein, refers to a chemical moiety having theformula N(R)₂, wherein each R is independently selected from hydrogenand (C₁-C₄)alkyl.

The term “aryl,” alone or in combination, as used herein, means anaromatic hydrocarbon radical of 6-18 carbon atoms (i.e., 6-18-memberedaryl) derived by the removal of hydrogen atom from a carbon atom of aparent aromatic ring system. In some instances, an aryl group has 6-12carbon atoms (i.e., 6-12-membered aryl). Some aryl groups arerepresented in the exemplary structures as “Ar.” Aryl includes bicyclicradicals comprising an aromatic ring fused to a saturated, partiallyunsaturated ring, or aromatic carbocyclic or heterocyclic ring. Inparticular embodiments, aryl is one, two or three rings. Typical arylgroups include, but are not limited to, radicals derived from benzene(phenyl), substituted benzenes, naphthalene (naphthyl), anthracene(anthryl) etc. Other aryl groups include, indanyl, biphenyl,phenanthryl, acenaphthyl and the like. Preferably, aryl is phenyl group.An aryl group can be optionally substituted as defined and describedherein.

The terms “cycloaliphatic,” “carbocyclyl,” “carbocyclo,” and“carbocyclic,” used alone or as part of a larger moiety, refer to aradical of a saturated or partially unsaturated cyclic aliphaticmonocyclic or bicyclic ring system, as described herein, having thespecified number of carbons. Exemplary carbocyclys have from 3 to 18carbon atoms, for example 3 to 12 carbon atoms, wherein the aliphaticring system is optionally substituted as defined and described herein.Bicyclic carbocycles having 7 to 12 atoms can be arranged, for example,as a bicyclo [4,5], [5,5], [5,6], or [6,6] system, and bicycliccarbocycles having 9 or 10 ring atoms can be arranged as a bicyclo [5,6]or [6,6] system, or as bridged systems such as bicyclo[2.2.1]heptane,bicyclo[2.2.2]octane and bicyclo[3.2.2]nonane. The aliphatic ring systemis optionally substituted as defined and described herein. Examples ofmonocyclic carbocycles include, but are not limited to, cycloalkyls andcycloalkenyls, such as cyclopropyl, cyclobutyl, cyclopentyl,1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl,1-cyclohex-1-enyl, l-cyclohex-2-enyl, 1-cyclohex-3-enyl,cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl,cycloundecyl, cyclododecyl, and the like. The terms “cycloaliphatic,”“carbocyclyl,” “carbocyclo,” and “carbocyclic” also include aliphaticrings that are fused to one or more aromatic or nonaromatic rings, suchas decahydronaphthyl, tetrahydronaphthyl, decalin, orbicyclo[2.2.2]octane.

The terms “cyclic alkyl” and “cycloalkyl” can be used interchangeably.They refer to a saturated carbocyclic ring radical of the specifiednumber of carbons. Typically, the cyclic alkyl is a 3-7-memberedmonocyclic ring radical. Examples of cycloalkyl include, but are notlimited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, andcycloheptyl. In some embodiments, cycloalkyl can optionally besubstituted with one or more substituents selected from OH, SH, halogen,amino, nitro, cyano, C₁-C₁₂ alkyl, C₂-C₁₂ alkenyl or C₂-C₁₂ alkynylgroup, C₁-C₁₂ alkoxy, C₁-C₁₂ haloalkyl, and C₁-C₁₂ haloalkoxy.

The term “cyclic alkenyl” refers to a carbocyclic ring radical havingthe specified number of carbons and having at least one double bond inthe ring structure.

The term “cyclic alkynyl” refers to a carbocyclic ring radical havingthe specified number of carbons and having at least one triple bond inthe ring structure.

The term “halo” or “halogen” as used herein means halogen and includes,for example, and without being limited thereto, fluoro, chloro, bromo,iodo and the like, in both radioactive and non-radioactive forms. In apreferred embodiment, halo is selected from the group consisting offluoro, chloro and bromo.

The term “haloalkyl”, as used herein, includes an alkyl substituted withone or more F, Cl, Br, or I, wherein alkyl is defined above.

The term “heteroaryl”, as used herein, refers to an aromatic radical of5-18 ring atoms (i.e., a 5-18-membered heteroaryl), containing one ormore heteroatoms independently selected from nitrogen, oxygen, andsulfur. A heteroaryl group can be monocyclic or polycyclic, e.g. amonocyclic heteroaryl ring fused to one or more carbocyclic aromaticgroups or other monocyclic heteroaryl groups. The heteroaryl groups ofthis invention can also include ring systems substituted with one ormore oxo moieties. In one aspect, heteroaryl has from 5-15 ring atoms(i.e., 5-15-membered heteroaryl), such as a 5-12-membered ring and,typically, has 5 or 6 ring atoms (i.e., a 5-6-membered-heteroaryl). Incertain instances, heteroaryl is a 5-membered heteroaryl and in otherinstances heteroaryl is a 6-membered heteroaryl. Examples of heteroarylgroups include, but are not limited to, pyridinyl, pyridazinyl,imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, quinolyl,isoquinolyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl,oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl,benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl,phthalazinyl, pyridazinyl, triazinyl, isoindolyl, purinyl, oxadiazolyl,thiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl,benzotriazolyl, benzothiazolyl, benzoxazolyl, quinazolinyl,quinoxalinyl, naphthyridinyl, dihydroquinolyl, tetrahydroquinolyl,dihydroisoquinolyl, tetrahydroisoquinolyl, benzofuryl, furopyridinyl,pyrolopyrimidinyl, and azaindolyl. The foregoing heteroaryl groups maybe C-attached or N-attached (where such is possible). For instance, agroup derived from pyrrole may be pyrrol-1-yl (N-attached) orpyrrol-3-yl (C-attached). A heteroaryl group can be optionallysubstituted as defined and described herein.

The terms “heterocycle,” “heterocyclyl,” and “heterocyclic ring” areused interchangeably herein and refer to a saturated or a partiallyunsaturated (i.e., having one or more double and/or triple bonds withinthe ring) carbocyclic radical of the specified number of carbons.Typically the heterocyclyl has from 3 to 18 ring atoms (i.e., a3-18-membered-heterocyclyl) in which at least one ring atom is aheteroatom selected nitrogen, oxygen and sulfur, the remaining ringatoms being C, where one or more ring atoms is optionally substitutedindependently with one or more substituents described herein. Typicalheterocyclyls have from 3-12 ring atoms (i.e., 3-12-memberedheterocyclyl). In some instance, heterocyclyls have from 4-7 ring atoms(i.e., 4-7-membered heterocyclyl. When one heteroatom is S, it can beoptionally mono or dioxygenated (i.e. S(O) or S(O)₂). The heterocyclylcan be monocyclic or polycyclic, in which case the rings can be attachedtogether in a pendent manner or can be fused or Spiro. A heterocycle maybe a monocycle having 3 to 7 ring members (2 to 6 carbon atoms and 1 to4 heteroatoms selected from N, O, and S) or a bicycle having 7 to 10ring members (4 to 9 carbon atoms and 1 to 6 heteroatoms selected fromN, O, and S), for example: a bicyclo [4,5], [5,5], [5,6], or [6,6]system. Heterocycles are described in Paquette, Leo A.; Principles ofModern Heterocyclic Chemistry (W. A. Benjamin, New York, 1968),particularly Chapters 1, 3, 4, 6, 7, and 9; The Chemistry ofHeterocyclic Compounds, A series of Monographs (John Wiley & Sons, NewYork, 1950 to present), in particular Volumes 13, 14, 16, 19, and 28;and J. Am. Chem. Soc. (1960) 82:5566. “Heterocyclyl” also includesradicals where heterocycle radicals are fused with a saturated,partially unsaturated ring, or aromatic carbocyclic or heterocyclicring, Examples of heterocyclic rings include, but are not limited to,pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl,tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidino,morpholino, thiomorpholino, thioxanyl, piperazinyl, homopiperazinyl,azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl,oxazepinyl, diazepinyl, thiazepinyl, 2-pyrrolinyl, 3-pyrrolinyl,indolinyl 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl,dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl,pyrazolidinylimidazolinyl, imidazolidinyl, 3-azabicyco[3.1.0]hexanyl,3-azabicyclo[4.1.0]heptanyl, and azabicyclo[2.2.2]hexanyl. Spiromoieties are also included within the scope of this definition. Examplesof a heterocyclic group wherein ring atoms are substituted with oxomoieties are pyrimidinonyl and 1,1-dioxo-thiomorpholinyl.

The heterocycle or heteroaryl groups may be carbon (carbon-linked) ornitrogen (nitrogen-linked) attached where such is possible. By way ofexample and not limitation, carbon bonded heterocycles or heteroarylsare bonded at position 2, 3, 4, 5, or 6 of a pyridine, position 3, 4, 5,or 6 of a pyridazine, position 2, 4, 5, or 6 of a pyrimidine, position2, 3, 5, or 6 of a pyrazine, position 2, 3, 4, or 5 of a furan,tetrahydrofuran, thiofuran, thiophene, pyrrole or tetrahydropyrrole,position 2, 4, or 5 of an oxazole, imidazole or thiazole, position 3, 4,or 5 of an isoxazole, pyrazole, or isothiazole, position 2 or 3 of anaziridine, position 2, 3, or 4 of an azetidine, position 2, 3, 4, 5, 6,7, or 8 of a quinoline or position 1, 3, 4, 5, 6, 7, or 8 of anisoquinoline.

By way of example and not limitation, nitrogen bonded heterocycles orheteroaryls are bonded at position 1 of an aziridine, azetidine,pyrrole, pyrrolidine, 2-pyrroline, 3-pyrroline, imidazole,imidazolidine, 2-imidazoline, 3-imidazoline, pyrazole, pyrazoline,2-pyrazoline, 3-pyrazoline, piperidine, piperazine, indole, indoline,1H-indazole, position 2 of a isoindole, or isoindoline, position 4 of amorpholine, and position 9 of a carbazole, or O-carboline.

The heteroatoms present in heteroaryl or heterocyclcyl include theoxidized forms such as NO, SO, and SO₂.

“Hydroxyl” means OH.

“Oxo” means ═O.

“Thioalkoxy” means S-alkyl, wherein alkyl is defined as above.

The alkyl, alkenyl, alkynyl, cyclic alkyl, cyclic alkenyl, cyclicalkynyl, carbocyclyl, aryl, heterocyclyl and heteroaryl described abovecan be optionally substituted with one or more (e.g., 2, 3, 4, 5, 6 ormore) substituents.

If a substituent is described as being “substituted,” a non-hydrogensubstituent is in the place of a hydrogen substituent on a carbon,oxygen, sulfur or nitrogen of the substituent. Thus, for example, asubstituted alkyl substituent is an alkyl substituent wherein at leastone non-hydrogen substituent is in the place of a hydrogen substituenton the alkyl substituent. To illustrate, monofluoroalkyl is alkylsubstituted with a fluoro substituent, and difluoroalkyl is alkylsubstituted with two fluoro substituents. It should be recognized thatif there is more than one substitution on a substituent, eachnon-hydrogen substituent may be identical or different (unless otherwisestated).

It is understood that substituents and substitution patterns on thecompounds of the invention can be selected by one of ordinary skill inthe art to provide compounds that are chemically stable and that can bereadily synthesized by techniques known in the art, as well as thosemethods set forth below. If a substituent is described as being“optionally substituted,” the substituent may be either (1) notsubstituted, or (2) substituted. If a carbon of a substituent isdescribed as being optionally substituted with one or more of a list ofsubstituents, one or more of the hydrogens on the carbon may separatelyand/or together be replaced with an independently selected optionalsubstituent. If a nitrogen of a substituent is described as beingoptionally substituted with one or more of a list of substituents, oneor more of the hydrogens on the nitrogen may each be replaced with anindependently selected optional substituent.

This specification uses the terms “substituent,” “radical,” and groupinterchangeably.

Combinations of substituents envisioned by this invention are preferablythose that result in the formation of stable or chemically feasiblecompounds. If a substituent is itself substituted with more than onegroup, it is understood that these multiple groups can be on the samecarbon atom or on different carbon atoms, as long as a stable structureresults. The term “stable,” as used herein, refers to compounds that arenot substantially altered when subjected to conditions to allow fortheir production, detection, and, in certain embodiments, theirrecovery, purification, and use for one or more of the purposesdisclosed herein.

Suitable monovalent substituents on a substitutable carbon atom of an“optionally substituted group” are independently halogen;—(CH₂)₀₋₄R^(∘); —(CH₂)₀₋₄OR^(∘); —O(CH₂)₀₋₄R^(∘), —O—(CH₂)₀₋₄C(O)OR^(∘);—(CH₂)₀₋₄CH(OR^(∘) ₂; —(CH₂)₀₋₄SR^(∘); —(CH₂)₀₋₄Ph, which may besubstituted with R^(∘); —(CH₂)₀₋₄O(CH₂)₀₋₁Ph which may be substitutedwith R^(∘); —CH═CHPh, which may be substituted with R^(∘);—(CH₂)₀₋₄O(CH₂)₀₋₁-pyridyl which may be substituted with R^(∘); —NO₂;—CN; —N₃; —(CH₂)₀₋₄N(R^(∘) ₂; —(CH₂)₀₋₄N(R^(∘)C(O)R^(∘);—N(R^(∘))C(S)R^(∘); —(CH₂)₀₋₄N(R^(∘))C(O)NR^(∘))₂; —N(R^(∘))C(S)NR^(∘)₂; —(CH₂)₀₋₄N(R^(∘))C(O)OR^(∘); —N(R^(∘))N(R^(∘))C(O)R^(∘);—N(R^(∘))N(R^(∘))C(O)NR^(∘) ₂; —N(R^(∘))N(R^(∘))C(O)OR^(∘);—(CH₂)₀₋₄C(O)R^(∘); —C(S)R^(∘); —(CH₂)₀₋₄C(O)OR^(∘);—(CH₂)₀₋₄C(O)SR^(∘); —(CH₂)₀₋₄C(O)OSiR^(∘) ₃; —(CH₂)₀₋₄C(O)R^(∘);—OC(O)(CH₂)₀₋₄SR^(∘), SC(S)SR^(∘); —(CH₂)₀₋₄SC(O)R^(∘);—(CH₂)₀₋₄C(O)NR^(∘) ₂; —C(S)NR^(∘) ₂; —C(S)SR^(∘); —SC(S)SR^(∘),—(CH₂)₀₋₄C(O)NR^(∘) ₂; —C(O)N(OR^(∘))R^(∘); —C(O)C(O)R^(∘);—C(O)CH₂C(O)R^(∘); —C(NOR^(∘))R^(∘); —(CH₂)₀₋₄SSR^(∘);—(CH₂)₀₋₄S(O)₂R^(∘); —(CH₂)₀₋₄S(O)₂OR^(∘); —(CH₂)₀₋₄S(O)₂R^(∘);—S(O)₂NR^(∘) ₂; —(CH₂)₀₋₄S(O)R^(∘); —N(R^(∘)S(O)₂NR^(∘) ₂;—N(R^(∘)S(O)₂R^(∘); —N(OR^(∘))R^(∘); —C(NH)NR^(∘) ₂; —P(O)₂R^(∘);—P(O)R^(∘) ₂; —OP(O)R^(∘) ₂; —OP(O)(OR^(∘))₂; SiR^(∘) ₃; —(C₁₋₄ straightor branched)alkylene)O—N(R^(∘))₂; or —(C₁₋₄ straight or branched)alkylene)C(O)O—N(R^(∘))₂, wherein each R^(∘) may be substituted asdefined below and is independently hydrogen, C₁₋₆ aliphatic, —CH₂Ph,—O(CH₂)₀₋₁Ph, —CH₂-(5-6 membered heteroaryl ring), or a 5-6-memberedsaturated, partially unsaturated, or aryl ring having 0-4 heteroatomsindependently selected from nitrogen, oxygen, and sulfur, or,notwithstanding the definition above, two independent occurrences ofR^(∘), taken together with their intervening atom(s), form a3-12-membered saturated, partially unsaturated, or aryl monocyclic orbicyclic ring having 0-4 heteroatoms independently selected fromnitrogen, oxygen, and sulfur, which may be substituted as defined below.

Suitable monovalent substituents on R^(∘) (or the ring formed by takingtwo independent occurrences of R^(∘) together with their interveningatoms), are independently halogen, —(CH₂)₀₋₂R^(●), -(haloR^(●)),—(CH₂)₀₋₂OH, —(CH₂)₀₋₂OR^(●), —(CH₂)₀₋₂CH(OR^(●))₂; —O(haloR^(●)), —CN,—N₃, —(CH₂)₀₋₂C(O)R^(●), —(CH₂)₀₋₂C(O)OH, —(CH₂)₀₋₂C(O)OR^(●),—(CH₂)₀₋₂SR^(●), —(CH₂)₀₋₂SH, —(CH₂)₀₋₂NH₂, —(CH₂)₀₋₂NHR^(●),—(CH₂)₀₋₂NR^(●) ₂, —NO₂, —OSiR^(●) ₃, —C(O)SR^(●), —(C₁₋₄ straight orbranched alkylene)C(O)OR^(●), or —SSR^(●) wherein each R′ isunsubstituted or where preceded by “halo” is substituted only with oneor more halogens, and is independently selected from C₁₋₄ aliphatic,—CH₂Ph, —O(CH₂)₀₋₁Ph, or a 5-6-membered saturated, partiallyunsaturated, or aryl ring having 0-4 heteroatoms independently selectedfrom nitrogen, oxygen, and sulfur. Suitable divalent substituents on asaturated carbon atom of R^(∘) include ═O and ═S.

Suitable divalent substituents on a saturated carbon atom of an“optionally substituted group” include the following: ═O, ═S, ═NNR*₂,═NNHC(O)R*, ═NNHC(O)OR*, —NNHS(O)₂R*, —NR*, —NOR*, —O(C(R^(*) ₂))₂₋₃O—,and —S(C(R^(*) ₂))₂₋₃S—, wherein each independent occurrence of R* isselected from hydrogen, C₁₋₆ aliphatic which may be substituted asdefined below, or an unsubstituted 5-6-membered saturated, partiallyunsaturated, or aryl ring having 0-4 heteroatoms independently selectedfrom nitrogen, oxygen, and sulfur. Suitable divalent substituents thatare bound to vicinal substitutable carbons of an “optionallysubstituted” group include: —O(CR*₂)₂₋₃O—, wherein each independentoccurrence of R* is selected from hydrogen, C₁₋₆ aliphatic which may besubstituted as defined below, or an unsubstituted 5-6-memberedsaturated, partially unsaturated, or aryl ring having 0-4 heteroatomsindependently selected from nitrogen, oxygen, and sulfur.

Suitable substituents on the aliphatic group of R* include halogen,—R^(●), -(haloR^(●)), —OH, —OR^(●), —O(haloR^(●)), —CN, —C(O)OH,—C(O)OR^(●), —NH₂, —NHR^(●), —NR^(●) ₂, and —NO₂, wherein each R^(●) isunsubstituted or where preceded by “halo” is substituted only with oneor more halogens, and is independently C₁₋₄ aliphatic, —CH₂Ph,—O(CH₂)₀₋₁Ph, or a 5-6-membered saturated, partially unsaturated, oraryl ring having 0-4 heteroatoms independently selected from nitrogen,oxygen, and sulfur.

Suitable substituents on a substitutable nitrogen of an “optionallysubstituted group” include —R^(†), —NR^(†) ₂, —C(O)R^(†), —C(O)OR^(†),—C(O)C(O)R^(†), —C(O)CH₂C(O)R^(†), —S(O)₂R^(†), —S(O)₂NR^(†) ₂,—C(S)NR^(†) ₂, —C(NH)NR^(†) ₂, and —N(R^(†))S(O)₂R^(†); wherein eachR^(†) is independently hydrogen, C₁₋₆ aliphatic which may be substitutedas defined below, unsubstituted —OPh, or an unsubstituted 5-6-memberedsaturated, partially unsaturated, or aryl ring having 0-4 heteroatomsindependently selected from nitrogen, oxygen, and sulfur, or,notwithstanding the definition above, two independent occurrences ofR^(†), taken together with their intervening atom(s) form anunsubstituted 3-12-membered saturated, partially unsaturated, or arylmonocyclic or bicyclic ring having 0-4 heteroatoms independentlyselected from nitrogen, oxygen, and sulfur.

Suitable substituents on the aliphatic group of R^(†) are independentlyhalogen, —R^(●), -(haloR^(●)), —OH, —OR^(●), —O(haloR^(●)), —CN,—C(O)OH, —C(O)OR^(●), —NH₂, —NHR^(●), —NR^(●) ₂, or —NO₂, wherein eachR^(●) is unsubstituted or where preceded by “halo” is substituted onlywith one or more halogens, and is independently C₁₋₄ aliphatic, —CH₂Ph,—O(CH₂)₀₋₁Ph, or a 5-6-membered saturated, partially unsaturated, oraryl ring having 0-4 heteroatoms independently selected from nitrogen,oxygen, and sulfur.

Preferred substituents on heteroaryl can be selected from the groupconsisting of —OH, —SH, nitro, halogen, amino, cyano, C₁-C₁₂ alkyl,C₂-C₁₂ alkenyl, C₂-C₁₂ alkynyl, C₁-C₁₂ alkoxy, C₁-C₁₂ haloalkyl, C₁-C₁₂haloalkoxy and C₁-C₁₂ thioalkoxy. Preferred substituents on alkyl,alkylene and heterocyclyl include the preferred substituents onheteroaryl and oxo. In one embodiment, the substituent on an alkyl,alkylene, heterocyclyl or heteroaryl is an amino group having theformula —N(R)₂, wherein each R is independently selected from hydrogenand C₁-C₄ alkyl.

The term “stereoisomer” refers to compounds which have identicalchemical constitution and connectivity, but different orientations oftheir atoms in space that cannot interconverted by rotation about singlebonds.

“Diastereomer” refers to a stereoisomer with two or more centers ofchirality and whose molecules are not mirror images of one another.Diastereomers have different physical properties, e.g. melting points,boiling points, spectral properties, and reactivities. Mixtures ofdiastereomers may separate under high resolution analytical proceduressuch as crystallization, electrophoresis and chromatography.

“Enantiomers” refer to two stereoisomers of a compound which arenon-superimposable mirror images of one another.

Stereochemical definitions and conventions used herein generally followS. P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984)McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S.,Stereochemistry of Organic Compounds, John Wiley & Sons, Inc., New York,1994. The compounds of the invention may contain asymmetric or chiralcenters, and therefore exist in different stereoisomeric forms. It isintended that all stereoisomeric forms of the compounds of theinvention, including but not limited to, diastereomers, enantiomers andatropisomers, as well as mixtures thereof such as racemic mixtures, formpart of the present invention. Many organic compounds exist in opticallyactive forms, i.e., they have the ability to rotate the plane ofplane-polarized light. In describing an optically active compound, theprefixes D and L, or R and S, are used to denote the absoluteconfiguration of the molecule about its chiral center(s). The prefixes dand I or (+) and (−) are employed to designate the sign of rotation ofplane-polarized light by the compound, with (−) or l meaning that thecompound is levorotatory. A compound prefixed with (+) or d isdextrorotatory. For a given chemical structure, these stereoisomers areidentical except that they are mirror images of one another. A specificstereoisomer may also be referred to as an enantiomer, and a mixture ofsuch isomers is often called an enantiomeric mixture. A 50:50 mixture ofenantiomers is referred to as a racemic mixture or a racemate, which mayoccur where there has been no stereo selection or stereo specificity ina chemical reaction or process. The terms “racemic mixture” and“racemate” refer to an equimolar mixture of two enantiomeric species,devoid of optical activity.

The term “tautomer” or “tautomeric form” refers to structural isomers ofdifferent energies which are interconvertible via a low energy barrier.For example, proton tautomers (also known as prototropic tautomers)include interconversions via migration of a proton, such as keto-enoland imine-enamine isomerizations. Valence tautomers includeinterconversions by reorganization of some of the bonding electrons.

Unless otherwise stated, structures depicted herein are also meant toinclude all isomeric (e.g., enantiomeric, diastereomeric, and geometric(or conformational)) forms of the structure; for example, the R and Sconfigurations for each asymmetric center, Z and E double bond isomers,and Z and E conformational isomers. Therefore, single stereoisomers aswell as enantiomeric, diastereomeric, and geometric (or conformational)mixtures of the present compounds are within the scope of the invention.Unless otherwise stated, all tautomeric forms of the compounds of theinvention are within the scope of the invention.

Unless specifically indicated (by a chemical name or other indicatordesignating double bond geometry, for example), each structural formulaused herein is meant to include compounds having a carbon-carbon doublebond (e.g., an exocyclic double bond) with a configuration that is cis(or Z), trans (or E), or a mixture of cis and trans. For example,formula I:

is meant to denote both:

and mixtures thereof.

As used herein, “exocyclic double bond” refers to the carbon-carbondouble bond in a compound of formula I indicated with an arrow in thefollowing structure:

In some embodiments described herein, the exocyclic double bond is in acis configuration. In other embodiments, the exocyclic double bond is ina trans configuration.

The Exemplification reflects whether the exocyclic double bond in agiven compound exists in a cis or trans configuration by indicating theconfiguration of the exocyclic double bond in the chemical nameassociated with the given compound.

As used herein, “cis” or “cis configuration” refers to a carbon-carbondouble bond, typically an exocyclic double bond, that is predominantlycis. In some embodiments, greater than about 85% of compound moleculesin a mixture of the compound have a carbon-carbon double bond (e.g., anexocyclic double bond) that is cis. In some embodiments, greater thanabout 90%, greater than about 95%, greater than about 98%, greater thanabout 99%, greater than about 99.5% or greater than about 99.8% ofcompound molecules in a mixture of the compound have a carbon-carbondouble bond (e.g., an exocyclic double bond) that is cis.

As used herein, “trans” or “trans configuration” refers to acarbon-carbon double bond, typically an exocyclic double bond, that ispredominantly trans. In some embodiments, greater than about 85% ofcompound molecules in a mixture of the compound have a carbon-carbondouble bond (e.g., an exocyclic double bond) that is cis. In someembodiments, greater than about 90%, greater than about 95%, greaterthan about 98%, greater than about 99%, greater than about 99.5% orgreater than about 99.8% of compound molecules in a mixture of thecompound have a carbon-carbon double bond (e.g., an exocyclic doublebond) that is cis.

Additionally, unless otherwise stated, structures depicted herein arealso meant to include compounds that differ only in the presence of oneor more isotopically enriched atoms. For example, compounds having thepresent structures including the replacement of hydrogen by deuterium ortritium, or the replacement of a carbon by a ¹³C- or ¹⁴C-enriched carbonare within the scope of this invention. Such compounds are useful, forexample, as analytical tools, as probes in biological assays, or astherapeutic agents in accordance with the present invention.

The term “pharmaceutically acceptable salt” means either an acidaddition salt or a basic addition salt which is compatible with thetreatment of patients.

In some embodiments, exemplary inorganic acids which form suitable saltsinclude, but are not limited thereto, hydrochloric, hydrobromic,sulfuric and phosphoric acid and acid metal salts such as sodiummonohydrogen orthophosphate and potassium hydrogen sulfate. Illustrativeorganic acids which form suitable salts include the mono-, di- andtricarboxylic acids. Illustrative of such acids are, for example,acetic, trifluoroacetic acid (2,2,2-trifluoroacetic acid), glycolic,lactic, pyruvic, malonic, succinic, glutaric, fumaric, malic, tartaric,citric, ascorbic, maleic, hydroxymaleic, benzoic, hydroxybenzoic,phenylacetic, cinnamic, salicylic, 2-phenoxybenzoic, p-toluenesulfonicacid and other sulfonic acids such as methanesulfonic acid and2-hydroxyethanesulfonic acid. Either the mono- or di-acid salts can beformed, and such salts can exist in either a hydrated, solvated orsubstantially anhydrous form. In general, the acid addition salts ofthese compounds are more soluble in water and various hydrophilicorganic solvents, and generally demonstrate higher melting points incomparison to their free base forms. Other non-pharmaceuticallyacceptable salts, e.g., oxalates may be used, for example, in theisolation of compounds described herein for laboratory use, or forsubsequent conversion to a pharmaceutically acceptable acid additionsalt.

A “pharmaceutically acceptable basic addition salt” is any non-toxicorganic or inorganic base addition salt of the acid compounds describedherein or any of its intermediates. Illustrative inorganic bases whichform suitable salts include, but are not limited thereto, lithium,sodium, potassium, calcium, magnesium or barium hydroxides. Illustrativeorganic bases which form suitable salts include aliphatic, alicyclic oraromatic organic amines such as methylamine, trimethyl amine andpicoline or ammonia. The selection of the appropriate salt may beimportant so that an ester functionality, if any, elsewhere in themolecule is not hydrolyzed. The selection criteria for the appropriatesalt will be known to one skilled in the art.

Acid addition salts of the compounds described herein are most suitablyformed from pharmaceutically acceptable acids, and include, for example,those formed with inorganic acids, e.g., hydrochloric, sulphuric orphosphoric acids and organic acids, e.g., succinic, maleic, acetic,trifluoroacetic or fumaric acid. Other non-pharmaceutically acceptablesalts, e.g., oxalates may be used for example in the isolation ofcompounds described herein for laboratory use, or for subsequentconversion to a pharmaceutically acceptable acid addition salt. Alsoincluded within the scope of the invention are base addition salts (suchas sodium, potassium and ammonium salts), solvates and hydrates ofcompounds of the invention. The conversion of a given compound salt to adesired compound salt is achieved by applying standard techniques, wellknown to one skilled in the art.

The term “treat” or “treating” means to alleviate symptoms, eliminatethe causation of the symptoms either on a temporary or permanent basis,or to prevent or slow the appearance of symptoms of the named disorderor condition.

As used herein, “promoting wound healing” means treating a subject witha wound and achieving healing, either partially or fully, of the wound.Promoting wound healing can mean, e.g., one or more of the following:promoting epidermal closure; promoting migration of the dermis;promoting dermal closure in the dermis; reducing wound healingcomplications, e.g., hyperplasia of the epidermis and adhesions;reducing wound dehiscence; and promoting proper scab formation.

The term “therapeutically effective amount” means that amount of activecompound that elicits the desired biological response in a subject. Suchresponse includes alleviation of the symptoms of the disease or disorderbeing treated, prevention, inhibition or a delay in the recurrence of asymptom of the disease or of the disease itself, an increase in thelongevity of the subject compared with the absence of the treatment, orprevention, inhibition or delay in the progression of symptom of thedisease or of the disease itself. Determination of the effective amountis well within the capability of those skilled in the art. Toxicity andtherapeutic efficacy of the compounds of the invention can be determinedby standard pharmaceutical procedures in cell cultures and inexperimental animals. The effective amount of compound of the presentinvention or other therapeutic agent to be administered to a subjectwill depend on the stage, category and status of the disease or disorderbeing treated and characteristics of the subject, such as generalhealth, age, sex, body weight and drug tolerance. The effective amountof compound of the present invention or other therapeutic agent to beadministered will also depend on administration route and dosage form.Dosage amount and interval can be adjusted individually to provideplasma levels of the active compound that are sufficient to maintaindesired therapeutic effects.

The term “pharmaceutically acceptable carrier” means a non-toxicsolvent, dispersant, excipient, adjuvant or other material which ismixed with the active ingredient in order to permit the formation of apharmaceutical composition, i.e., a dosage form capable of beingadministered to a subject. One example of such a carrier ispharmaceutically acceptable oil typically used for parenteraladministration. Pharmaceutically acceptable carriers are well known inthe art.

When introducing elements disclosed herein, the articles “a”, “an”,“the”, and “said” are intended to mean that there are one or more of theelements. The terms “comprising”, “having”, “including” are intended tobe open-ended and mean that there may be additional elements other thanthe listed elements.

Uses, Formulation and Administration

Pharmaceutically Acceptable Compositions

According to another embodiment, the invention provides a compositioncomprising a compound of this invention or a pharmaceutically acceptablederivative thereof and a pharmaceutically acceptable carrier, adjuvant,or vehicle. The amount of compound in compositions of this invention issuch that is effective to measurably inhibit CRM1, in a biologicalsample or in a patient. In certain embodiments, a composition of thisinvention is formulated for administration to a patient in need of suchcomposition. The term “patient”, as used herein, means an animal. Insome embodiments, the animal is a mammal. In certain embodiments, thepatient is a veterinary patient (i.e., a non-human mammal patient). Insome embodiments, the patient is a dog. In other embodiments, thepatient is a human.

The term “pharmaceutically acceptable carrier, adjuvant, or vehicle”refers to a non-toxic carrier, adjuvant, or vehicle that does notdestroy the pharmacological activity of the compound with which it isformulated. Pharmaceutically acceptable carriers, adjuvants or vehiclesthat may be used in the compositions of this invention include, but arenot limited to, ion exchangers, alumina, aluminum stearate, lecithin,serum proteins, such as human serum albumin, buffer substances such asphosphates, glycine, sorbic acid, potassium sorbate, partial glyceridemixtures of saturated vegetable fatty acids, water, salts orelectrolytes, such as protamine sulfate, disodium hydrogen phosphate,potassium hydrogen phosphate, sodium chloride, zinc salts, colloidalsilica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-basedsubstances, polyethylene glycol, sodium carboxymethylcellulose,polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers,polyethylene glycol and wool fat.

Compositions of the present invention may be administered orally,parenterally (including subcutaneous, intramuscular, intravenous andintradermal), by inhalation spray, topically, rectally, nasally,buccally, vaginally or via an implanted reservoir. In some embodiments,provided compounds or compositions are administrable intravenouslyand/or intraperitoneally.

The term “parenteral” as used herein includes subcutaneous, intravenous,intramuscular, intraocular, intravitreal, intra-articular,intra-synovial, intrasternal, intrathecal, intrahepatic, intraperitonealintralesional and intracranial injection or infusion techniques.Preferably, the compositions are administered orally, subcutaneously,intraperitoneally or intravenously. Sterile injectable forms of thecompositions of this invention may be aqueous or oleaginous suspension.These suspensions may be formulated according to techniques known in theart using suitable dispersing or wetting agents and suspending agents.The sterile injectable preparation may also be a sterile injectablesolution or suspension in a non-toxic parenterally acceptable diluent orsolvent, for example as a solution in 1,3-butanediol. Among theacceptable vehicles and solvents that may be employed are water,Ringer's solution and isotonic sodium chloride solution. In addition,sterile, fixed oils are conventionally employed as a solvent orsuspending medium.

Pharmaceutically acceptable compositions of this invention may be orallyadministered in any orally acceptable dosage form including, but notlimited to, capsules, tablets, aqueous suspensions or solutions. In thecase of tablets for oral use, carriers commonly used include lactose andcorn starch. Lubricating agents, such as magnesium stearate, are alsotypically added. For oral administration in a capsule form, usefuldiluents include lactose and dried cornstarch. When aqueous suspensionsare required for oral use, the active ingredient is combined withemulsifying and suspending agents. If desired, certain sweetening,flavoring or coloring agents may also be added. In some embodiments, aprovided oral formulation is formulated for immediate release orsustained/delayed release. In some embodiments, the composition issuitable for buccal or sublingual administration, including tablets,lozenges and pastilles. A provided compound can also be inmicro-encapsulated form.

Alternatively, pharmaceutically acceptable compositions of thisinvention may be administered in the form of suppositories for rectaladministration. Pharmaceutically acceptable compositions of thisinvention may also be administered topically, especially when the targetof treatment includes areas or organs readily accessible by topicalapplication, including diseases of the eye, the skin, or the lowerintestinal tract. Suitable topical formulations are readily prepared foreach of these areas or organs.

Topical application for the lower intestinal tract can be effected in arectal suppository formulation (see above) or in a suitable enemaformulation. Topically-transdermal patches may also be used.

For ophthalmic use, provided pharmaceutically acceptable compositionsmay be formulated as micronized suspensions or in an ointment such aspetrolatum.

Pharmaceutically acceptable compositions of this invention may also beadministered by nasal aerosol or inhalation.

In some embodiments, pharmaceutically acceptable compositions of thisinvention are formulated for intra-peritoneal administration.

The amount of compounds of the present invention that may be combinedwith the carrier materials to produce a composition in a single dosageform will vary depending upon the host treated, the particular mode ofadministration. In one embodiment, provided compositions should beformulated so that a dosage of between 0.01-100 mg/kg body weight/day ofthe inhibitor can be administered to a patient receiving thesecompositions. In another embodiment, the dosage is from about 0.5 toabout 100 mg/kg of body weight, or between 1 mg and 1000 mg/dose, every4 to 120 hours, or according to the requirements of the particular drug.Typically, the pharmaceutical compositions of this invention will beadministered from about 1 to about 6 times per day.

It should also be understood that a specific dosage and treatmentregimen for any particular patient will depend upon a variety offactors, including the activity of the specific compound employed, theage, body weight, general health, sex, diet, time of administration,rate of excretion, drug combination, and the judgment of the treatingphysician and the severity of the particular disease being treated. Theamount of a compound of the present invention in the composition willalso depend upon the particular compound in the composition.

Upon improvement of a patient's condition, a maintenance dose of acompound, composition or combination of this invention may beadministered, if necessary. Subsequently, the dosage or frequency ofadministration, or both, may be reduced, as a function of the symptoms,to a level at which the improved condition is retained when the symptomshave been alleviated to the desired level. Patients may, however,require intermittent treatment on a long-term basis upon any recurrenceof disease symptoms

Uses of Compounds and Pharmaceutically Acceptable Compositions

Compounds and compositions described herein are generally useful for theinhibition of CRM1 and are therefore useful for treating one or moredisorders associated with activity of CRM1. Thus, in certainembodiments, the present invention provides a method for treating aCRM1-mediated disorder comprising the step of administering to a patientin need thereof a compound of the present invention, or pharmaceuticallyacceptable composition thereof. The compounds and compositions describedherein can also be administered to cells in culture, e.g. in vitro or exvivo, or to a subject, e.g., in vivo, to treat, prevent, and/or diagnosea variety of disorders, including those described herein below.

The activity of a compound utilized in this invention as an inhibitor ofCRM1 may be assayed in vitro, in vivo or in a cell line. Detailedconditions for assaying a compound utilized in this invention as aninhibitor of CRM1 are set forth in the Examples below.

As used herein, the term “CRM1-mediated” disorder or condition, as usedherein, means any disease or other deleterious condition in which CRM1is known to play a role. Accordingly, another embodiment of the presentinvention relates to treating or lessening the severity of one or morediseases in which CRM1 is known to play a role. In some embodiments, thepresent invention provides methods of treating a disease associated withexpression or activity of p53, p73, p21, pRB, p2′7, IκB, NFκB, c-Abl,FOXO proteins, COX-2, or an HDAC (histone deacetylases) in a subjectcomprising administering to the patient a therapeutically effectiveamount of a compound described herein. In another embodiment, thepresent invention relates to a method of treating or lessening theseverity of a disease or condition selected from a proliferativedisorder (e.g., cancer), an inflammatory disorder, an autoimmunedisorder, a viral infection, an ophthalmological disorder or aneurodegenerative disorder wherein said method comprises administeringto a patient in need thereof a compound or composition according to thepresent invention. In a more specific embodiment, the present inventionrelates to a method of treating or lessening the severity of cancer.Specific examples of the above disorders are set forth in detail below.

Cancers treatable by the compounds of this invention include, but arenot limited to, hematologic malignancies (leukemias, lymphomas, myelomasincluding multiple myeloma, myelodysplastic and myeloproliferativesyndromes) and solid tumors (carcinomas such as prostate, breast, lung,colon, pancreatic, renal, ovarian as well as soft tissue andosteosarcomas, and stromal tumors). Breast cancer (BC) can includebasal-like breast cancer (BLBC), triple negative breast cancer (TNBC)and breast cancer that is both BLBC and TNBC. In addition, breast cancercan include invasive or non-invasive ductal or lobular carcinoma,tubular, medullary, mucinous, papillary, cribriform carcinoma of thebreast, male breast cancer, recurrent or metastatic breast cancer,phyllodes tumor of the breast and Paget's disease of the nipple.

Inflammatory disorders treatable by the compounds of this inventioninclude, but are not limited to, multiple sclerosis, rheumatoidarthritis, degenerative joint disease, systemic lupus, systemicsclerosis, vasculitis syndromes (small, medium and large vessel),atherosclerosis, inflammatory bowel disease, irritable bowel syndrome,Crohn's disease, mucous colitis, ulcerative colitis, gastritis, sepsis,psoriasis and other dermatological inflammatory disorders (such aseczema, atopic dermatitis, contact dermatitis, urticaria, scleroderma,and dermatosis with acute inflammatory components, pemphigus,pemphigoid, allergic dermatitis), and urticarial syndromes.

Viral diseases treatable by the compounds of this invention include, butare not limited to, acute febrile pharyngitis, pharyngoconjunctivalfever, epidemic keratoconjunctivitis, infantile gastroenteritis,Coxsackie infections, infectious mononucleosis, Burkitt lymphoma, acutehepatitis, chronic hepatitis, hepatic cirrhosis, hepatocellularcarcinoma, primary HSV-1 infection (e.g., gingivostomatitis in children,tonsillitis and pharyngitis in adults, keratoconjunctivitis), latentHSV-1 infection (e.g., herpes labialis and cold sores), primary HSV-2infection, latent HSV-2 infection, aseptic meningitis, infectiousmononucleosis, Cytomegalic inclusion disease, Kaposi's sarcoma,multicentric Castleman disease, primary effusion lymphoma, AIDS,influenza, Reye syndrome, measles, postinfectious encephalomyelitis,Mumps, hyperplastic epithelial lesions (e.g., common, flat, plantar andanogenital warts, laryngeal papillomas, epidermodysplasiaverruciformis), cervical carcinoma, squamous cell carcinomas, croup,pneumonia, bronchiolitis, common cold, Poliomyelitis, Rabies,influenza-like syndrome, severe bronchiolitis with pneumonia, Germanmeasles, congenital rubella, Varicella, and herpes zoster. Viraldiseases treatable by the compounds of this invention also includechronic viral infections, including hepatitis B and hepatitis C.

Exemplary ophthalmology disorders include, but are not limited to,macular edema (diabetic and nondiabetic macular edema), aged relatedmacular degeneration wet and dry forms, aged disciform maculardegeneration, cystoid macular edema, palpebral edema, retina edema,diabetic retinopathy, chorioretinopathy, neovascular maculopathy,neovascular glaucoma, uveitis, iritis, retinal vasculitis,endophthalmitis, panophthalmitis, metastatic ophthalmia, choroiditis,retinal pigment epitheliitis, conjunctivitis, cyclitis, scleritis,episcleritis, optic neuritis, retrobulbar optic neuritis, keratitis,blepharitis, exudative retinal detachment, corneal ulcer, conjunctivalulcer, chronic nummular keratitis, ophthalmic disease associated withhypoxia or ischemia, retinopathy of prematurity, proliferative diabeticretinopathy, polypoidal choroidal vasculopathy, retinal angiomatousproliferation, retinal artery occlusion, retinal vein occlusion, Coats'disease, familial exudative vitreoretinopathy, pulseless disease(Takayasu's disease), Eales disease, antiphospholipid antibody syndrome,leukemic retinopathy, blood hyperviscosity syndrome, macroglobulinemia,interferon-associated retinopathy, hypertensive retinopathy, radiationretinopathy, corneal epithelial stem cell deficiency or cataract.

Neurodegenerative diseases treatable by a compound of Formula I include,but are not limited to, Parkinson's, Alzheimer's, and Huntington's, andAmyotrophic lateral sclerosis (ALS/Lou Gehrig's Disease).

Compounds and compositions described herein may also be used to treatdisorders of abnormal tissue growth and fibrosis including dilativecardiomyopathy, hypertrophic cardiomyopathy, restrictive cardiomyopathy,pulmonary fibrosis, hepatic fibrosis, glomerulonephritis, polycystickidney disorder (PKD) and other renal disorders.

Compounds and compositions described herein may also be used to treatdisorders related to food intake such as obesity and hyperphagia.

In another embodiment, a compound or composition described herein may beused to treat or prevent allergies and respiratory disorders, includingasthma, bronchitis, pulmonary fibrosis, allergic rhinitis, oxygentoxicity, emphysema, chronic bronchitis, acute respiratory distresssyndrome, and any chronic obstructive pulmonary disease (COPD).

In some embodiments, the disorder or condition associated with CRM1activity is beta thalassemia, muscular dystrophy, arthritis, forexample, osteoarthritis and rheumatoid arthritis, ankylosingspondilitis, traumatic brain injury, spinal cord injury, sepsis,rheumatic disease, cancer atherosclerosis, type 1 diabetes, type 2diabetes, leptospiriosis renal disease, glaucoma, retinal disease,ageing, headache, pain, complex regional pain syndrome, cardiachypertrophy, musclewasting, catabolic disorders, obesity, fetal growthretardation, hypercholesterolemia, heart disease, chronic heart failure,ischemia/reperfusion, stroke, cerebral aneurysm, angina pectoris,pulmonary disease, cystic fibrosis, acid-induced lung injury, pulmonaryhypertension, asthma, chronic obstructive pulmonary disease, Sjogren'ssyndrome, hyaline membrane disease, kidney disease, glomerular disease,alcoholic liver disease, gut diseases, peritoneal endometriosis, skindiseases, nasal sinusitis, mesothelioma, anhidrotic ecodermaldysplasia-ID, behcet's disease, incontinentia pigmenti, tuberculosis,asthma, crohn's disease, colitis, ocular allergy, appendicitis, paget'sdisease, pancreatitis, periodonitis, endometriosis, inflammatory boweldisease, inflammatory lung disease, silica-induced diseases, sleepapnea, AIDS, HIV-1, autoimmune diseases, antiphospholipid syndrome,lupus, lupus nephritis, familial mediterranean fever, hereditaryperiodic fever syndrome, psychosocial stress diseases, neuropathologicaldiseases, familial amyloidotic polyneuropathy, inflammatory neuropathy,parkinson's disease, multiple sclerosis, alzheimer's disease, amyotropiclateral sclerosis, huntington's disease, cataracts, or hearing loss.

In other embodiments, the disorder or condition associated with CRM1activity is head injury, uveitis, inflammatory pain, allergen inducedasthma, non-allergen induced asthma, glomerular nephritis, ulcerativecolitis, necrotizing enterocolitis, hyperimmunoglobulinemia D withrecurrent fever (HIDS), TNF receptor associated periodic syndrome(TRAPS), cryopyrin-associated periodic syndromes, Muckle-Wells syndrome(urticaria deafness amyloidosis), familial cold urticaria, neonatalonset multisystem inflammatory disease (NOMID), periodic fever, aphthousstomatitis, pharyngitis and adenitis (PFAPA syndrome), Blau syndrome,pyogenic sterile arthritis, pyoderma gangrenosum, acne (PAPA),deficiency of the interleukin-1-receptor antagonist (DIRA), subarachnoidhemorrhage, polycystic kidney disease, transplant, organ transplant,tissue transplant, myelodysplastic syndrome, irritant-inducedinflammation, plant irritant-induced inflammation, poison ivy/urushioloil-induced inflammation, chemical irritant-induced inflammation, beesting-induced inflammation, insect bite-induced inflammation, sunburn,burns, dermatitis, endotoxemia, lung injury, acute respiratory distresssyndrome, alcoholic hepatitis, or kidney injury caused by parasiticinfections.

In further aspects, the present invention provides a use of a compounddescribed herein for the manufacture of a medicament for the treatmentof a disease associated with expression or activity of p53, p73, p21,pRB, p2′7, IκB, NFκB, c-Abl, FOXO proteins, COX-2 or an HDAC in asubject. In some embodiments, the present invention provides a use of acompound described herein in the manufacture of a medicament for thetreatment of any of cancer and/or neoplastic disorders, angiogenesis,autoimmune disorders, inflammatory disorders and/or diseases,epigenetics, hormonal disorders and/or diseases, viral diseases,neurodegenerative disorders and/or diseases, wounds, and ophthalmologicdisorders.

In some embodiments, the present invention provides a method forinhibiting CRM1 in a biological sample comprising contacting thebiological sample with, or administering to the patient, apharmaceutically acceptable salt of a compound of the invention, orpharmaceutically acceptable composition thereof.

Neoplastic Disorders

A compound or composition described herein can be used to treat aneoplastic disorder. A “neoplastic disorder” is a disease or disordercharacterized by cells that have the capacity for autonomous growth orreplication, e.g., an abnormal state or condition characterized byproliferative cell growth. Exemplary neoplastic disorders include:carcinoma, sarcoma, metastatic disorders, e.g., tumors arising fromprostate, brain, bone, colon, lung, breast, ovarian, and liver origin,hematopoietic neoplastic disorders, e.g., leukemias, lymphomas, myelomaand other malignant plasma cell disorders, and metastatic tumors.Prevalent cancers include: breast, prostate, colon, lung, liver, andpancreatic cancers. Treatment with the compound can be in an amounteffective to ameliorate at least one symptom of the neoplastic disorder,e.g., reduced cell proliferation, reduced tumor mass, etc.

The disclosed methods are useful in the prevention and treatment ofcancer, including for example, solid tumors, soft tissue tumors, andmetastases thereof, as well as in familial cancer syndromes such as LiFraumeni Syndrome, Familial Breast-Ovarian Cancer (BRCA1 or BRAC2mutations) Syndromes, and others. The disclosed methods are also usefulin treating non-solid cancers. Exemplary solid tumors includemalignancies (e.g., sarcomas, adenocarcinomas, and carcinomas) of thevarious organ systems, such as those of lung, breast, lymphoid,gastrointestinal (e.g., colon), and genitourinary (e.g., renal,urothelial, or testicular tumors) tracts, pharynx, prostate, and ovary.Exemplary adenocarcinomas include colorectal cancers, renal-cellcarcinoma, liver cancer, non-small cell carcinoma of the lung, andcancer of the small intestine.

Exemplary cancers described by the National Cancer Institute include:Acute Lymphoblastic Leukemia, Adult; Acute Lymphoblastic Leukemia,Childhood; Acute Myeloid Leukemia, Adult; Adrenocortical Carcinoma;Adrenocortical Carcinoma, Childhood; AIDS-Related Lymphoma; AIDS-RelatedMalignancies; Anal Cancer; Astrocytoma, Childhood Cerebellar;Astrocytoma, Childhood Cerebral; Bile Duct Cancer, Extrahepatic; BladderCancer; Bladder Cancer, Childhood; Bone Cancer, Osteosarcoma/MalignantFibrous Histiocytoma; Brain Stem Glioma, Childhood; Brain Tumor, Adult;Brain Tumor, Brain Stem Glioma, Childhood; Brain Tumor, CerebellarAstrocytoma, Childhood; Brain Tumor, Cerebral Astrocytoma/MalignantGlioma, Childhood; Brain Tumor, Ependymoma, Childhood; Brain Tumor,Medulloblastoma, Childhood; Brain Tumor, Supratentorial PrimitiveNeuroectodermal Tumors, Childhood; Brain Tumor, Visual Pathway andHypothalamic Glioma, Childhood; Brain Tumor, Childhood (Other); BreastCancer; Breast Cancer and Pregnancy; Breast Cancer, Childhood; BreastCancer, Male; Bronchial Adenomas/Carcinoids, Childhood; Carcinoid Tumor,Childhood; Carcinoid Tumor, Gastrointestinal; Carcinoma, Adrenocortical;Carcinoma, Islet Cell; Carcinoma of Unknown Primary; Central NervousSystem Lymphoma, Primary; Cerebellar Astrocytoma, Childhood; CerebralAstrocytoma/Malignant Glioma, Childhood; Cervical Cancer; ChildhoodCancers; Chronic Lymphocytic Leukemia; Chronic Myelogenous Leukemia;Chronic Myeloproliferative Disorders; Clear Cell Sarcoma of TendonSheaths; Colon Cancer; Colorectal Cancer, Childhood; Cutaneous T-CellLymphoma; Endometrial Cancer; Ependymoma, Childhood; Epithelial Cancer,Ovarian; Esophageal Cancer (e.g., esophageal squamous cell cancer);Esophageal Cancer, Childhood; Ewing's Family of Tumors; ExtracranialGerm Cell Tumor, Childhood; Extragonadal Germ Cell Tumor; ExtrahepaticBile Duct Cancer; Eye Cancer, Intraocular Melanoma; Eye Cancer,Retinoblastoma; Gallbladder Cancer; Gastric (Stomach) Cancer; Gastric(Stomach) Cancer, Childhood; Gastrointestinal Carcinoid Tumor; Germ CellTumor, Extracranial, Childhood; Germ Cell Tumor, Extragonadal; Germ CellTumor, Ovarian; Gestational Trophoblastic Tumor; Glioma, Childhood BrainStem; Glioma, Childhood Visual Pathway and Hypothalamic; Hairy CellLeukemia; Head and Neck Cancer; Hepatocellular (Liver) Cancer, Adult(Primary); Hepatocellular (Liver) Cancer, Childhood (Primary); Hodgkin'sLymphoma, Adult; Hodgkin's Lymphoma, Childhood; Hodgkin's LymphomaDuring Pregnancy; Hypopharyngeal Cancer; Hypothalamic and Visual PathwayGlioma, Childhood; Intraocular Melanoma; Islet Cell Carcinoma (EndocrinePancreas); Kaposi's Sarcoma; Kidney Cancer; Laryngeal Cancer; LaryngealCancer, Childhood; Leukemia, Acute Lymphoblastic, Adult; Leukemia, AcuteLymphoblastic, Childhood; Leukemia, Acute Myeloid, Adult; Leukemia,Acute Myeloid, Childhood; Leukemia, Chronic Lymphocytic; Leukemia,Chronic Myelogenous; Leukemia, Hairy Cell; Lip and Oral Cavity Cancer;Liver Cancer, Adult (Primary); Liver Cancer, Childhood (Primary); LungCancer, Non-Small Cell; Lung Cancer, Small Cell; Lymphoblastic Leukemia,Adult Acute; Lymphoblastic Leukemia, Childhood Acute; LymphocyticLeukemia, Chronic; Lymphoma, AIDS-Related; Lymphoma, Central NervousSystem (Primary); Lymphoma, Cutaneous T-Cell; Lymphoma, Hodgkin's,Adult; Lymphoma, Hodgkin's, Childhood; Lymphoma, Hodgkin's DuringPregnancy; Lymphoma, Non-Hodgkin's, Adult; Lymphoma, Non-Hodgkin's,Childhood; Lymphoma, Non-Hodgkin's During Pregnancy; Lymphoma, PrimaryCentral Nervous System; Macroglobulinemia, Waldenstrom's; Male BreastCancer; Malignant Mesothelioma, Adult; Malignant Mesothelioma,Childhood; Malignant Thymoma; Medulloblastoma, Childhood; Melanoma;Melanoma, Intraocular; Merkel Cell Carcinoma; Mesothelioma, Malignant;Metastatic Squamous Neck Cancer with Occult Primary; Multiple EndocrineNeoplasia Syndrome, Childhood; Multiple Myeloma/Plasma Cell Neoplasm;Mycosis Fungoides; Myelodysplastic Syndromes; Myelogenous Leukemia,Chronic; Myeloid Leukemia, Childhood Acute; Myeloma, Multiple;Myeloproliferative Disorders, Chronic; Nasal Cavity and Paranasal SinusCancer; Nasopharyngeal Cancer; Nasopharyngeal Cancer, Childhood;Neuroblastoma; Non-Hodgkin's Lymphoma, Adult; Non-Hodgkin's Lymphoma,Childhood; Non-Hodgkin's Lymphoma During Pregnancy; Non-Small Cell LungCancer; Oral Cancer, Childhood; Oral Cavity and Lip Cancer;Oropharyngeal Cancer; Osteosarcoma/Malignant Fibrous Histiocytoma ofBone; Ovarian Cancer, Childhood; Ovarian Epithelial Cancer; Ovarian GermCell Tumor; Ovarian Low Malignant Potential Tumor; Pancreatic Cancer;Pancreatic Cancer, Childhood; Pancreatic Cancer, Islet Cell; ParanasalSinus and Nasal Cavity Cancer; Parathyroid Cancer; Penile Cancer;Pheochromocytoma; Pineal and Supratentorial Primitive NeuroectodermalTumors, Childhood; Pituitary Tumor; Plasma Cell Neoplasm/MultipleMyeloma; Pleuropulmonary Blastoma; Pregnancy and Breast Cancer;Pregnancy and Hodgkin's Lymphoma; Pregnancy and Non-Hodgkin's Lymphoma;Primary Central Nervous System Lymphoma; Primary Liver Cancer, Adult;Primary Liver Cancer, Childhood; Prostate Cancer; Rectal Cancer; RenalCell (Kidney) Cancer; Renal Cell Cancer, Childhood; Renal Pelvis andUreter, Transitional Cell Cancer; Retinoblastoma; Rhabdomyosarcoma,Childhood; Salivary Gland Cancer; Salivary Gland Cancer, Childhood;Sarcoma, Ewing's Family of Tumors; Sarcoma, Kaposi's; Sarcoma(Osteosarcoma)/Malignant Fibrous Histiocytoma of Bone; Sarcoma,Rhabdomyosarcoma, Childhood; Sarcoma, Soft Tissue, Adult; Sarcoma, SoftTissue, Childhood; Sezary Syndrome; Skin Cancer; Skin Cancer, Childhood;Skin Cancer (Melanoma); Skin Carcinoma, Merkel Cell; Small Cell LungCancer; Small Intestine Cancer; Soft Tissue Sarcoma, Adult; Soft TissueSarcoma, Childhood; Squamous Neck Cancer with Occult Primary,Metastatic; Stomach (Gastric) Cancer; Stomach (Gastric) Cancer,Childhood; Supratentorial Primitive Neuroectodermal Tumors, Childhood;T-Cell Lymphoma, Cutaneous; Testicular Cancer; Thymoma, Childhood;Thymoma, Malignant; Thyroid Cancer; Thyroid Cancer, Childhood;Transitional Cell Cancer of the Renal Pelvis and Ureter; TrophoblasticTumor, Gestational; Unknown Primary Site, Cancer of, Childhood; UnusualCancers of Childhood; Ureter and Renal Pelvis, Transitional Cell Cancer;Urethral Cancer; Uterine Sarcoma; Vaginal Cancer; Visual Pathway andHypothalamic Glioma, Childhood; Vulvar Cancer; Waldenstrom'sMacroglobulinemia; and Wilms' Tumor.

Further exemplary cancers include diffuse large B-cell lymphoma (DLBCL)and mantle cell lymphoma (MCL). Yet further exemplary cancers includeendocervical cancer, B-cell ALL, T-cell ALL, B- or T-cell lymphoma, mastcell cancer, glioblastoma, neuroblastoma, follicular lymphoma andRichter's syndrome.

Exemplary sarcomas include fibrosarcoma, alveolar soft part sarcoma(ASPS), liposarcoma, leiomyosarcoma, chondrosarcoma, synovial sarcoma,chordoma, spindle cell sarcoma, histiocytoma, rhabdomyosarcoma, Ewing'ssarcoma, neuroectodermal sarcoma, phyllodes/osteogenic sarcoma andchondroblastic osteosarcoma.

Metastases of the aforementioned cancers can also be treated orprevented in accordance with the methods described herein.

Combination Therapies

In some embodiments, a compound described herein is administeredtogether with an additional “second” therapeutic agent or treatment. Thechoice of second therapeutic agent may be made from any agent that istypically used in a monotherapy to treat the indicated disease orcondition. As used herein, the term “administered together” and relatedterms refers to the simultaneous or sequential administration oftherapeutic agents in accordance with this invention. For example, acompound of the present invention may be administered with anothertherapeutic agent simultaneously or sequentially in separate unit dosageforms or together in a single unit dosage form. Accordingly, the presentinvention provides a single unit dosage form comprising a compound ofthe invention, an additional therapeutic agent, and a pharmaceuticallyacceptable carrier, adjuvant, or vehicle.

In one embodiment of the invention, where a second therapeutic agent isadministered to a subject, the effective amount of the compound of thisinvention is less than its effective amount would be where the secondtherapeutic agent is not administered. In another embodiment, theeffective amount of the second therapeutic agent is less than itseffective amount would be where the compound of this invention is notadministered. In this way, undesired side effects associated with highdoses of either agent may be minimized. Other potential advantages(including without limitation improved dosing regimens and/or reduceddrug cost) will be apparent to those of skill in the art. The additionalagents may be administered separately, as part of a multiple doseregimen, from the compounds of this invention. Alternatively, thoseagents may be part of a single dosage form, mixed together with thecompounds of this invention in a single composition.

Cancer Combination Therapies

In some embodiments, a compound described herein is administeredtogether with an additional cancer treatment. Exemplary additionalcancer treatments include, for example: chemotherapy, targeted therapiessuch as antibody therapies, kinase inhibitors, immunotherapy, andhormonal therapy, epigenetic therapy, proteosome inhibitors (e.g.,carfilzomib), and anti-angiogenic therapies. Examples of each of thesetreatments are provided below. As used herein, the term “combination,”“combined,” and related terms refer to the simultaneous or sequentialadministration of therapeutic agents in accordance with this invention.For example, a compound of the present invention can be administeredwith another therapeutic agent simultaneously or sequentially inseparate unit dosage forms or together in a single unit dosage form.Accordingly, the present invention provides a single unit dosage formcomprising a compound of the invention, an additional therapeutic agent,and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

The amount of both a compound of the invention and additionaltherapeutic agent (in those compositions which comprise an additionaltherapeutic agent as described above) that can be combined with thecarrier materials to produce a single dosage form will vary dependingupon the host treated and the particular mode of administration.Preferably, compositions of this invention should be formulated so thata dosage of between 0.01-100 mg/kg body weight/day of a compound of theinvention can be administered.

Chemotherapy

In some embodiments, a compound described herein is administered with achemotherapy. Chemotherapy is the treatment of cancer with drugs thatcan destroy cancer cells. “Chemotherapy” usually refers to cytotoxicdrugs which affect rapidly dividing cells in general, in contrast withtargeted therapy. Chemotherapy drugs interfere with cell division invarious possible ways, e.g., with the duplication of DNA or theseparation of newly formed chromosomes. Most forms of chemotherapytarget all rapidly dividing cells and are not specific for cancer cells,although some degree of specificity may come from the inability of manycancer cells to repair DNA damage, while normal cells generally can.

Examples of chemotherapeutic agents used in cancer therapy include, forexample, antimetabolites (e.g., folic acid, purine, and pyrimidinederivatives) and alkylating agents (e.g., nitrogen mustards,nitrosoureas, platinum, alkyl sulfonates, hydrazines, triazenes,aziridines, spindle poison, cytotoxic agents, topoisomerase inhibitorsand others). Exemplary agents include Aclarubicin, Actinomycin,Alitretinoin, Altretamine, Aminopterin, Aminolevulinic acid, Amrubicin,Amsacrine, Anagrelide, Arsenic trioxide, Asparaginase, Atrasentan,Belotecan, Bexarotene, Bendamustin, Bleomycin, Bortezomib, Busulfan,Camptothecin, Capecitabine, Carboplatin, Carboquone, Carmofur,Carmustine, Celecoxib, Chlorambucil, Chlormethine, Cisplatin,Cladribine, Clofarabine, Crisantaspase, Cyclophosphamide, Cytarabine,Dacarbazine, Dactinomycin, Daunorubicin, Decitabine, Demecolcine,Docetaxel, Doxorubicin, Efaproxiral, Elesclomol, Elsamitrucin,Enocitabine, Epirubicin, Estramustine, Etoglucid, Etoposide,Floxuridine, Fludarabine, Fluorouracil (5FU), Fotemustine, Gemcitabine,Gliadel implants, Hydroxycarbamide, Hydroxyurea, Idarubicin, Ifosfamide,Irinotecan, Irofulven, Ixabepilone, Larotaxel, Leucovorin, Liposomaldoxorubicin, Liposomal daunorubicin, Lonidamine, Lomustine, Lucanthone,Mannosulfan, Masoprocol, Melphalan, Mercaptopurine, Mesna, Methotrexate,Methyl aminolevulinate, Mitobronitol, Mitoguazone, Mitotane, Mitomycin,Mitoxantrone, Nedaplatin, Nimustine, Oblimersen, Omacetaxine, Ortataxel,Oxaliplatin, Paclitaxel, Pegaspargase, Pemetrexed, Pentostatin,Pirarubicin, Pixantrone, Plicamycin, Porfimer sodium, Prednimustine,Procarbazine, Raltitrexed, Ranimustine, Rubitecan, Sapacitabine,Semustine, Sitimagene ceradenovec, Strataplatin, Streptozocin,Talaporfin, Tegafur-uracil, Temoporfin, Temozolomide, Teniposide,Tesetaxel, Testolactone, Tetranitrate, Thiotepa, Tiazofurine,Tioguanine, Tipifarnib, Topotecan, Trabectedin, Triaziquone,Triethylenemelamine, Triplatin, Tretinoin, Treosulfan, Trofosfamide,Uramustine, Valrubicin, Verteporfin, Vinblastine, Vincristine,Vindesine, Vinflunine, Vinorelbine, Vorinostat, Zorubicin, and othercytostatic or cytotoxic agents described herein.

Because some drugs work better together than alone, two or more drugsare often given at the same time. Often, two or more chemotherapy agentsare used as combination chemotherapy. In some embodiments, thechemotherapy agents (including combination chemotherapy) can be used incombination with a compound described herein.

Targeted Therapy

Targeted therapy constitutes the use of agents specific for thederegulated proteins of cancer cells. Small molecule targeted therapydrugs are generally inhibitors of enzymatic domains on mutated,overexpressed, or otherwise critical proteins within the cancer cell.Prominent examples are the tyrosine kinase inhibitors such as Axitinib,Bosutinib, Cediranib, desatinib, erolotinib, imatinib, gefitinib,lapatinib, Lestaurtinib, Nilotinib, Semaxanib, Sorafenib, Sunitinib, andVandetanib, and also cyclin-dependent kinase inhibitors such asAlvocidib and Seliciclib. Monoclonal antibody therapy is anotherstrategy in which the therapeutic agent is an antibody whichspecifically binds to a protein on the surface of the cancer cells.Examples include the anti-HER2/neu antibody trastuzumab (Herceptin®)typically used in breast cancer, and the anti-CD20 antibody rituximaband Tositumomab typically used in a variety of B-cell malignancies.Other exemplary antibodies include Cetuximab, Panitumumab, Trastuzumab,Alemtuzumab, Bevacizumab, Edrecolomab, and Gemtuzumab. Exemplary fusionproteins include Aflibercept and Denileukin diftitox. In someembodiments, the targeted therapy can be used in combination with acompound described herein, e.g., Gleevec (Vignari and Wang 2001).

Targeted therapy can also involve small peptides as “homing devices”which can bind to cell surface receptors or affected extracellularmatrix surrounding the tumor. Radionuclides which are attached to thesepeptides (e.g., RGDs) eventually kill the cancer cell if the nuclidedecays in the vicinity of the cell. An example of such therapy includesBEXXAR®.

Angiogenesis

Compounds and methods described herein may be used to treat or prevent adisease or disorder associated with angiogenesis. Diseases associatedwith angiogenesis include cancer, cardiovascular disease and maculardegeneration.

Angiogenesis is the physiological process involving the growth of newblood vessels from pre-existing vessels. Angiogenesis is a normal andvital process in growth and development, as well as in wound healing andin granulation tissue. However, it is also a fundamental step in thetransition of tumors from a dormant state to a malignant one.Angiogenesis may be a target for combating diseases characterized byeither poor vascularisation or abnormal vasculature.

Application of specific compounds that may inhibit or induce thecreation of new blood vessels in the body may help combat such diseases.The presence of blood vessels where there should be none may affect themechanical properties of a tissue, increasing the likelihood of failure.The absence of blood vessels in a repairing or otherwise metabolicallyactive tissue may inhibit repair or other essential functions. Severaldiseases, such as ischemic chronic wounds, are the result of failure orinsufficient blood vessel formation and may be treated by a localexpansion of blood vessels, thus bringing new nutrients to the site,facilitating repair. Other diseases, such as age-related maculardegeneration, may be created by a local expansion of blood vessels,interfering with normal physiological processes.

Vascular endothelial growth factor (VEGF) has been demonstrated to be amajor contributor to angiogenesis, increasing the number of capillariesin a given network. Upregulation of VEGF is a major component of thephysiological response to exercise and its role in angiogenesis issuspected to be a possible treatment in vascular injuries. In vitrostudies clearly demonstrate that VEGF is a potent stimulator ofangiogenesis because, in the presence of this growth factor, platedendothelial cells will proliferate and migrate, eventually forming tubestructures resembling capillaries.

Tumors induce blood vessel growth (angiogenesis) by secreting variousgrowth factors (e.g., VEGF). Growth factors such as bFGF and VEGF caninduce capillary growth into the tumor, which some researchers suspectsupply required nutrients, allowing for tumor expansion.

Angiogenesis represents an excellent therapeutic target for thetreatment of cardiovascular disease. It is a potent, physiologicalprocess that underlies the natural manner in which our bodies respond toa diminution of blood supply to vital organs, namely the production ofnew collateral vessels to overcome the ischemic insult.

Overexpression of VEGF causes increased permeability in blood vessels inaddition to stimulating angiogenesis. In wet macular degeneration, VEGFcauses proliferation of capillaries into the retina. Since the increasein angiogenesis also causes edema, blood and other retinal fluids leakinto the retina, causing loss of vision.

Anti-angiogenic therapy can include kinase inhibitors targeting vascularendothelial growth factor (VEGF) such as sunitinib, sorafenib, ormonoclonal antibodies or receptor “decoys” to VEGF or VEGF receptorincluding bevacizumab or VEGF-Trap, or thalidomide or its analogs(lenalidomide, pomalidomide), or agents targeting non-VEGF angiogenictargets such as fibroblast growth factor (FGF), angiopoietins, orangiostatin or endostatin.

Epigenetics

Compounds and methods described herein may be used to treat or prevent adisease or disorder associated with epigenetics. Epigenetics is thestudy of heritable changes in phenotype or gene expression caused bymechanisms other than changes in the underlying DNA sequence. Oneexample of epigenetic changes in eukaryotic biology is the process ofcellular differentiation. During morphogenesis, stem cells become thevarious cell lines of the embryo which in turn become fullydifferentiated cells. In other words, a single fertilized egg cellchanges into the many cell types including neurons, muscle cells,epithelium, blood vessels etc. as it continues to divide. It does so byactivating some genes while inhibiting others.

Epigenetic changes are preserved when cells divide. Most epigeneticchanges only occur within the course of one individual organism'slifetime, but, if a mutation in the DNA has been caused in sperm or eggcell that results in fertilization, then some epigenetic changes areinherited from one generation to the next. Specific epigenetic processesinclude paramutation, bookmarking, imprinting, gene silencing, Xchromosome inactivation, position effect, reprogramming, transvection,maternal effects, the progress of carcinogenesis, many effects ofteratogens, regulation of histone modifications and heterochromatin, andtechnical limitations affecting parthenogenesis and cloning.

Exemplary diseases associated with epigenetics include ATR-syndrome,fragile X-syndrome, ICF syndrome, Angelman's syndrome, Prader-Willssyndrome, BWS, Rett syndrome, α-thalassaemia, cancer, leukemia,Rubinstein-Taybi syndrome and Coffin-Lowry syndrome.

The first human disease to be linked to epigenetics was cancer.Researchers found that diseased tissue from patients with colorectalcancer had less DNA methylation than normal tissue from the samepatients. Because methylated genes are typically turned off, loss of DNAmethylation can cause abnormally high gene activation by altering thearrangement of chromatin. On the other hand, too much methylation canundo the work of protective tumor suppressor genes.

DNA methylation occurs at CpG sites, and a majority of CpG cytosines aremethylated in mammals. However, there are stretches of DNA near promoterregions that have higher concentrations of CpG sites (known as CpGislands) that are free of methylation in normal cells. These CpG islandsbecome excessively methylated in cancer cells, thereby causing genesthat should not be silenced to turn off. This abnormality is thetrademark epigenetic change that occurs in tumors and happens early inthe development of cancer. Hypermethylation of CpG islands can causetumors by shutting off tumor-suppressor genes. In fact, these types ofchanges may be more common in human cancer than DNA sequence mutations.

Furthermore, although epigenetic changes do not alter the sequence ofDNA, they can cause mutations. About half of the genes that causefamilial or inherited forms of cancer are turned off by methylation.Most of these genes normally suppress tumor formation and help repairDNA, including 06-methylguanine-DNA methyltransferase (MGMT), MLH1cyclin-dependent kinase inhibitor 2B (CDKN2B), and RASSF1A. For example,hypermethylation of the promoter of MGMT causes the number of G-to-Amutations to increase.

Hypermethylation can also lead to instability of microsatellites, whichare repeated sequences of DNA. Microsatellites are common in normalindividuals, and they usually consist of repeats of the dinucleotide CA.Too much methylation of the promoter of the DNA repair gene MLH1 canmake a microsatellite unstable and lengthen or shorten it.Microsatellite instability has been linked to many cancers, includingcolorectal, endometrial, ovarian, and gastric cancers.

Fragile X syndrome is the most frequently inherited mental disability,particularly in males. Both sexes can be affected by this condition, butbecause males only have one X chromosome, one fragile X will impact themmore severely. Indeed, fragile X syndrome occurs in approximately 1 in4,000 males and 1 in 8,000 females. People with this syndrome havesevere intellectual disabilities, delayed verbal development, and“autistic-like” behavior.

Fragile X syndrome gets its name from the way the part of the Xchromosome that contains the gene abnormality looks under a microscope;it usually appears as if it is hanging by a thread and easily breakable.The syndrome is caused by an abnormality in the FMR1 (fragile X mentalretardation 1) gene. People who do not have fragile X syndrome have 6 to50 repeats of the trinucleotide CGG in their FMR1 gene. However,individuals with over 200 repeats have a full mutation, and they usuallyshow symptoms of the syndrome. Too many CGGs cause the CpG islands atthe promoter region of the FMR1 gene to become methylated; normally,they are not. This methylation turns the gene off, stopping the FMR1gene from producing an important protein called fragile X mentalretardation protein. Loss of this specific protein causes fragile Xsyndrome. Although a lot of attention has been given to the CGGexpansion mutation as the cause of fragile X, the epigenetic changeassociated with FMR1 methylation is the real syndrome culprit.

Fragile X syndrome is not the only disorder associated with mentalretardation that involves epigenetic changes. Other such conditionsinclude Rubenstein-Taybi, Coffin-Lowry, Prader-Willi, Angelman,Beckwith-Wiedemann, ATR-X, and Rett syndromes.

Epigenetic therapies include inhibitors of enzymes controllingepigenetic modifications, specifically DNA methyltransferases andhistone deacetylases, which have shown promising anti-tumorigeniceffects for some malignancies, as well as antisense oligonucleotides andsiRNA.

Immunotherapy

In some embodiments, a compound described herein is administered with animmunotherapy. Cancer immunotherapy refers to a diverse set oftherapeutic strategies designed to induce the patient's own immunesystem to fight the tumor. Contemporary methods for generating an immuneresponse against tumors include intravesicular BCG immunotherapy forsuperficial bladder cancer, prostate cancer vaccine Provenge, and use ofinterferons and other cytokines to induce an immune response in renalcell carcinoma and melanoma patients.

Allogeneic hematopoietic stem cell transplantation can be considered aform of immunotherapy, since the donor's immune cells will often attackthe tumor in a graft-versus-tumor effect. In some embodiments, theimmunotherapy agents can be used in combination with a compounddescribed herein.

Hormonal Therapy

In some embodiments, a compound described herein is administered with ahormonal therapy. The growth of some cancers can be inhibited byproviding or blocking certain hormones. Common examples ofhormone-sensitive tumors include certain types of breast and prostatecancers, as well as certain types of leukemia which respond to certainretinoids/retinoic acids. Removing or blocking estrogen or testosteroneis often an important additional treatment. In certain cancers,administration of hormone agonists, such as progestogens may betherapeutically beneficial. In some embodiments, the hormonal therapyagents can be used in combination with a compound described herein.

Hormonal therapy agents include the administration of hormone agonistsor hormone antagonists and include retinoids/retinoic acid, compoundsthat inhibit estrogen or testosterone, as well as administration ofprogestogens.

Inflammation and Autoimmune Disease

The compounds and methods described herein may be used to treat orprevent a disease or disorder associated with inflammation, particularlyin humans and other mammals. A compound described herein may beadministered prior to the onset of, at, or after the initiation ofinflammation. When used prophylactically, the compounds are preferablyprovided in advance of any inflammatory response or symptom.Administration of the compounds can prevent or attenuate inflammatoryresponses or symptoms. Exemplary inflammatory conditions include, forexample, multiple sclerosis, rheumatoid arthritis, psoriatic arthritis,degenerative joint disease, spondouloarthropathies, other seronegativeinflammatory arthridities, polymyalgia rheumatica, various vasculidities(e.g., giant cell arteritis, ANCA+ vasculitis), gouty arthritis,systemic lupus erythematosus, juvenile arthritis, juvenile rheumatoidarthritis, osteoarthritis, osteoporosis, diabetes (e.g., insulindependent diabetes mellitus or juvenile onset diabetes), menstrualcramps, cystic fibrosis, inflammatory bowel disease, irritable bowelsyndrome, Crohn's disease, mucous colitis, ulcerative colitis,gastritis, esophagitis, pancreatitis, peritonitis, Alzheimer's disease,shock, ankylosing spondylitis, gastritis, conjunctivitis, pancreatis(acute or chronic), multiple organ injury syndrome (e.g., secondary tosepticemia or trauma), myocardial infarction, atherosclerosis, stroke,reperfusion injury (e.g., due to cardiopulmonary bypass or kidneydialysis), acute glomerulonephritis, thermal injury (i.e., sunburn),necrotizing enterocolitis, granulocyte transfusion associated syndrome,and/or Sjogren's syndrome. Exemplary inflammatory conditions of the skininclude, for example, eczema, atopic dermatitis, contact dermatitis,urticaria, schleroderma, psoriasis, and dermatosis with acuteinflammatory components.

In another embodiment, a compound or method described herein may be usedto treat or prevent allergies and respiratory conditions, includingasthma, bronchitis, pulmonary fibrosis, allergic rhinitis, oxygentoxicity, emphysema, chronic bronchitis, acute respiratory distresssyndrome, and any chronic obstructive pulmonary disease (COPD). Thecompounds may be used to treat chronic hepatitis infection, includinghepatitis B and hepatitis C.

Additionally, a compound or method described herein may be used to treatautoimmune diseases and/or inflammation associated with autoimmunediseases, such as organ-tissue autoimmune diseases (e.g., Raynaud'ssyndrome), scleroderma, myasthenia gravis, transplant rejection,endotoxin shock, sepsis, psoriasis, eczema, dermatitis, multiplesclerosis, autoimmune thyroiditis, uveitis, systemic lupuserythematosis, Addison's disease, autoimmune polyglandular disease (alsoknown as autoimmune polyglandular syndrome), and Grave's disease.

In a particular embodiment, the compounds described herein can be usedto treat multiple sclerosis.

Combination Therapy

In certain embodiments, a compound described herein may be administeredalone or in combination with other compounds useful for treating orpreventing inflammation. Exemplary anti-inflammatory agents include, forexample, steroids (e.g., Cortisol, cortisone, fludrocortisone,prednisone, 6[alpha]-methylprednisone, triamcinolone, betamethasone ordexamethasone), nonsteroidal antiinflammatory drugs (NSAIDS (e.g.,aspirin, acetaminophen, tolmetin, ibuprofen, mefenamic acid, piroxicam,nabumetone, rofecoxib, celecoxib, etodolac or nimesulide). In anotherembodiment, the other therapeutic agent is an antibiotic (e.g.,vancomycin, penicillin, amoxicillin, ampicillin, cefotaxime,ceftriaxone, cefixime, rifampinmetronidazole, doxycycline orstreptomycin). In another embodiment, the other therapeutic agent is aPDE4 inhibitor (e.g., roflumilast or rolipram). In another embodiment,the other therapeutic agent is an antihistamine (e.g., cyclizine,hydroxyzine, promethazine or diphenhydramine). In another embodiment,the other therapeutic agent is an anti-malarial (e.g., artemisinin,artemether, artsunate, chloroquine phosphate, mefloquine hydrochloride,doxycycline hyclate, proguanil hydrochloride, atovaquone orhalofantrine). In one embodiment, the other compound is drotrecoginalfa.

Further examples of anti-inflammatory agents include, for example,aceclofenac, acemetacin, e-acetamidocaproic acid, acetaminophen,acetaminosalol, acetanilide, acetylsalicylic acid, S-adenosylmethionine,alclofenac, alclometasone, alfentanil, algestone, allylprodine,alminoprofen, aloxiprin, alphaprodine, aluminum bis(acetylsalicylate),amcinonide, amfenac, aminochlorthenoxazin, 3-amino-4-hydroxybutyricacid, 2-amino-4-picoline, aminopropylon, aminopyrine, amixetrine,ammonium salicylate, ampiroxicam, amtolmetin guacil, anileridine,antipyrine, antrafenine, apazone, beclomethasone, bendazac, benorylate,benoxaprofen, benzpiperylon, benzydamine, benzylmorphine, bermoprofen,betamethasone, betamethasone-17-valerate, bezitramide,[alpha]-bisabolol, bromfenac, p-bromoacetanilide, 5-bromosalicylic acidacetate, bromosaligenin, bucetin, bucloxic acid, bucolome, budesonide,bufexamac, bumadizon, buprenorphine, butacetin, butibufen, butorphanol,carbamazepine, carbiphene, caiprofen, carsalam, chlorobutanol,chloroprednisone, chlorthenoxazin, choline salicylate, cinchophen,cinmetacin, ciramadol, clidanac, clobetasol, clocortolone, clometacin,clonitazene, clonixin, clopirac, cloprednol, clove, codeine, codeinemethyl bromide, codeine phosphate, codeine sulfate, cortisone,cortivazol, cropropamide, crotethamide, cyclazocine, deflazacort,dehydrotestosterone, desomorphine, desonide, desoximetasone,dexamethasone, dexamethasone-21-isonicotinate, dexoxadrol,dextromoramide, dextropropoxyphene, deoxycorticosterone, dezocine,diampromide, diamorphone, diclofenac, difenamizole, difenpiramide,diflorasone, diflucortolone, diflunisal, difluprednate, dihydrocodeine,dihydrocodeinone enol acetate, dihydromorphine, dihydroxyaluminumacetylsalicylate, dimenoxadol, dimepheptanol, dimethylthiambutene,dioxaphetyl butyrate, dipipanone, diprocetyl, dipyrone, ditazol,droxicam, emorfazone, enfenamic acid, enoxolone, epirizole, eptazocine,etersalate, ethenzamide, ethoheptazine, ethoxazene,ethylmethylthiambutene, ethylmorphine, etodolac, etofenamate,etonitazene, eugenol, felbinac, fenbufen, fenclozic acid, fendosal,fenoprofen, fentanyl, fentiazac, fepradinol, feprazone, floctafenine,fluazacort, flucloronide, flufenamic acid, flumethasone, flunisolide,flunixin, flunoxaprofen, fluocinolone acetonide, fluocinonide,fluocinolone acetonide, fluocortin butyl, fluocoitolone, fluoresone,fluorometholone, fluperolone, flupirtine, fluprednidene,fluprednisolone, fluproquazone, flurandrenolide, flurbiprofen,fluticasone, formocortal, fosfosal, gentisic acid, glafenine,glucametacin, glycol salicylate, guaiazulene, halcinonide, halobetasol,halometasone, haloprednone, heroin, hydrocodone, hydro cortamate,hydrocortisone, hydrocortisone acetate, hydrocortisone succinate,hydrocortisone hemi succinate, hydrocortisone 21-lysinate,hydrocortisone cypionate, hydromorphone, hydroxypethidine, ibufenac,ibuprofen, ibuproxam, imidazole salicylate, indomethacin, indoprofen,isofezolac, isoflupredone, isoflupredone acetate, isoladol,isomethadone, isonixin, isoxepac, isoxicam, ketobemidone, ketoprofen,ketorolac, p-lactophenetide, lefetamine, levallorphan, levorphanol,levophenacyl-morphan, lofentanil, lonazolac, lornoxicam, loxoprofen,lysine acetylsalicylate, mazipredone, meclofenamic acid, medrysone,mefenamic acid, meloxicam, meperidine, meprednisone, meptazinol,mesalamine, metazocine, methadone, methotrimeprazine,methylprednisolone, methylprednisolone acetate, methylprednisolonesodium succinate, methylprednisolone suleptnate, metiazinic acid,metofoline, metopon, mofebutazone, mofezolac, mometasone, morazone,morphine, morphine hydrochloride, morphine sulfate, morpholinesalicylate, myrophine, nabumetone, nalbuphine, nalorphine, 1-naphthylsalicylate, naproxen, narceine, nefopam, nicomorphine, nifenazone,niflumic acid, nimesulide, 5′-nitro-2′-propoxyacetanilide,norlevorphanol, normethadone, normorphine, norpipanone, olsalazine,opium, oxaceprol, oxametacine, oxaprozin, oxycodone, oxymorphone,oxyphenbutazone, papaveretum, paramethasone, paranyline, parsalmide,pentazocine, perisoxal, phenacetin, phenadoxone, phenazocine,phenazopyridine hydrochloride, phenocoll, phenoperidine, phenopyrazone,phenomorphan, phenyl acetylsalicylate, phenylbutazone, phenylsalicylate, phenyramidol, piketoprofen, piminodine, pipebuzone,piperylone, pirazolac, piritramide, piroxicam, pirprofen, pranoprofen,prednicarbate, prednisolone, prednisone, prednival, prednylidene,proglumetacin, proheptazine, promedol, propacetamol, properidine,propiram, propoxyphene, propyphenazone, proquazone, protizinic acid,proxazole, ramifenazone, remifentanil, rimazolium metilsulfate,salacetamide, salicin, salicylamide, salicylamide o-acetic acid,salicylic acid, salicylsulfuric acid, salsalate, salverine, simetride,sufentanil, sulfasalazine, sulindac, superoxide dismutase, suprofen,suxibuzone, talniflumate, tenidap, tenoxicam, terofenamate, tetrandrine,thiazolinobutazone, tiaprofenic acid, tiaramide, tilidine, tinoridine,tixocortol, tolfenamic acid, tolmetin, tramadol, triamcinolone,triamcinolone acetonide, tropesin, viminol, xenbucin, ximoprofen,zaltoprofen and zomepirac.

In one embodiment, a compound described herein may be administered witha selective COX-2 inhibitor for treating or preventing inflammation.Exemplary selective COX-2 inhibitors include, for example, deracoxib,parecoxib, celecoxib, valdecoxib, rofecoxib, etoricoxib, andlumiracoxib.

In some embodiments, a provided compound is administered in combinationwith an anthracycline or a Topo II inhibitor. In certain embodiments, aprovided compound is administered in combination with Doxorubicin (Dox).In certain embodiments, a provided compound is administered incombination with a proteasome inhibitor such as bortezomib orcarfilzomib.

Viral Infections

Compounds and methods described herein may be used to treat or prevent adisease or disorder associated with a viral infection, particularly inhumans and other mammals. A compound described herein may beadministered prior to the onset of, at, or after the initiation of viralinfection. When used prophylactically, the compounds are preferablyprovided in advance of any viral infection or symptom thereof.

Exemplary viral diseases include acute febrile pharyngitis,pharyngoconjunctival fever, epidemic keratoconjunctivitis, infantilegastroenteritis, Coxsackie infections, infectious mononucleosis, Burkittlymphoma, acute hepatitis, chronic hepatitis, hepatic cirrhosis,hepatocellular carcinoma, primary HSV-1 infection (e.g.,gingivostomatitis in children, tonsillitis and pharyngitis in adults,keratoconjunctivitis), latent HSV-1 infection (e.g., herpes labialis andcold sores), primary HSV-2 infection, latent HSV-2 infection, asepticmeningitis, infectious mononucleosis, Cytomegalic inclusion disease,Kaposi's sarcoma, multicentric Castleman disease, primary effusionlymphoma, AIDS, influenza, Reye syndrome, measles, postinfectiousencephalomyelitis, Mumps, hyperplastic epithelial lesions (e.g., common,flat, plantar and anogenital warts, laryngeal papillomas,epidermodysplasia verruciformis), cervical carcinoma, squamous cellcarcinomas, croup, pneumonia, bronchiolitis, common cold, Poliomyelitis,Rabies, influenza-like syndrome, severe bronchiolitis with pneumonia,German measles, congenital rubella, Varicella, and herpes zoster.

Exemplary viral influenza A strains include H1N1, H3N2, H5N1, H7N3,H7N9. A compound described herein can also be used to treat or preventinfluenza B.

Exemplary viral pathogens include Adenovirus, Coxsackievirus, Denguevirus, Encephalitis Virus, Epstein-Barr virus, Hepatitis A virus,Hepatitis B virus, Hepatitis C virus, Herpes simplex virus type 1,Herpes simplex virus type 2, cytomegalovirus, Human herpesvirus type 8,Human immunodeficiency virus, Influenza virus, measles virus, Mumpsvirus, Human papillomavirus, Parainfluenza virus, Poliovirus, Rabiesvirus, Respiratory syncytial virus, Rubella virus, Varicella-zostervirus, West Nile virus, Dungee, and Yellow fever virus. Viral pathogensmay also include viruses that cause resistant viral infections.

Antiviral drugs are a class of medications used specifically fortreating viral infections. Antiviral action generally falls into one ofthree mechanisms: interference with the ability of a virus to infiltratea target cell (e.g., amantadine, rimantadine and pleconaril), inhibitionof the synthesis of virus (e.g., nucleoside analogues, e.g., acyclovirand zidovudine (AZT), and inhibition of the release of virus (e.g.,zanamivir and oseltamivir).

Ophthalmology

Compounds and methods described herein may be used to treat or preventan ophthamology disorder. Exemplary ophthamology disorders includemacular edema (diabetic and nondiabetic macular edema), age relatedmacular degeneration wet and dry forms, aged disciform maculardegeneration, cystoid macular edema, palpebral edema, retina edema,diabetic retinopathy, chorioretinopathy, neovascular maculopathy,neovascular glaucoma, uveitis, iritis, retinal vasculitis,endophthalmitis, panophthalmitis, metastatic ophthalmia, choroiditis,retinal pigment epithelitis, conjunctivitis, cyclitis, scleritis,episcleritis, optic neuritis, retrobulbar optic neuritis, keratitis,blepharitis, exudative retinal detachment, corneal ulcer, conjunctivalulcer, chronic nummular keratitis, ophthalmic disease associated withhypoxia or ischemia, retinopathy of prematurity, proliferative diabeticretinopathy, polypoidal choroidal vasculopathy, retinal angiomatousproliferation, retinal artery occlusion, retinal vein occlusion, Coats'disease, familial exudative vitreoretinopathy, pulseless disease(Takayasu's disease), Eales disease, antiphospholipid antibody syndrome,leukemic retinopathy, blood hyperviscosity syndrome, macroglobulinemia,interferon-associated retinopathy, hypertensive retinopathy, radiationretinopathy, corneal epithelial stem cell deficiency and cataract.

Other ophthalmology disorders treatable using the compounds and methodsdescribed herein include proliferative vitreoretinopathy and chronicretinal detachment.

Inflammatory eye diseases are also treatable using the compounds andmethods described herein.

Neurodegenerative Disease

Neurodegeneration is the umbrella term for the progressive loss ofstructure or function of neurons, including death of neurons. Manyneurodegenerative diseases including Parkinson's, Alzheimer's, andHuntington's occur as a result of neurodegenerative processes. Asresearch progresses, many similarities appear which relate thesediseases to one another on a sub-cellular level. Discovering thesesimilarities offers hope for therapeutic advances that could amelioratemany diseases simultaneously. There are many parallels between differentneurodegenerative disorders including atypical protein assemblies aswell as induced cell death.

Alzheimer's disease is characterized by loss of neurons and synapses inthe cerebral cortex and certain subcortical regions. This loss resultsin gross atrophy of the affected regions, including degeneration in thetemporal lobe and parietal lobe, and parts of the frontal cortex andcingulate gyms.

Huntington's disease causes astrogliosis and loss of medium spinyneurons. Areas of the brain are affected according to their structureand the types of neurons they contain, reducing in size as theycumulatively lose cells. The areas affected are mainly in the striatum,but also the frontal and temporal cortices. The striatum's subthalamicnuclei send control signals to the globus pallidus, which initiates andmodulates motion. The weaker signals from subthalamic nuclei thus causereduced initiation and modulation of movement, resulting in thecharacteristic movements of the disorder. Exemplary treatments forHuntington's disease include tetrabenazine, neuroleptics,benzodiazepines, amantadine, remacemide, valproic acid, selectiveserotonin reuptake inhibitors (SSRIs), mirtazapine and antipsychotics.

The mechanism by which the brain cells in Parkinson's are lost mayconsist of an abnormal accumulation of the protein alpha-synuclein boundto ubiquitin in the damaged cells. The alpha-synuclein-ubiquitin complexcannot be directed to the proteosome. This protein accumulation formsproteinaceous cytoplasmic inclusions called Lewy bodies. The latestresearch on pathogenesis of disease has shown that the death ofdopaminergic neurons by alpha-synuclein is due to a defect in themachinery that transports proteins between two major cellularorganelles—the endoplasmic reticulum (ER) and the Golgi apparatus.Certain proteins like Rab1 may reverse this defect caused byalpha-synuclein in animal models. Exemplary Parkinson's diseasetherapies include levodopa, dopamine agonists such as includebromocriptine, pergolide, pramipexole, ropinirole, piribedil,cabergoline, apomorphine and lisuride, dopa decarboxylate inhibitors,MAO-B inhibitors such as selegilene and rasagilene, anticholinergics andamantadine.

Amyotrophic lateral sclerosis (ALS/Lou Gehrig's Disease) is a disease inwhich motor neurons are selectively targeted for degeneration. ExemplaryALS therapies include riluzole, baclofen, diazepam, trihexyphenidyl andamitriptyline.

Other exemplary neurodegenerative therapeutics include antisenseoligonucleotides and stem cells.

Wound Healing

Wounds are a type of condition characterized by cell or tissue damage.Wound healing is a dynamic pathway that optimally leads to restorationof tissue integrity and function. The wound healing process consists ofthree overlapping phases. The first phase is an inflammatory phase,which is characterized by homeostasis, platelet aggregation anddegranulation. Platelets as the first response, release multiple growthfactors to recruit immune cells, epithelial cells, and endothelialcells. The inflammatory phase typically occurs over days 0-5. The secondstage of wound healing is the proliferative phase during whichmacrophages and granulocytes invade the wound. Infiltrating fibroblastsbegin to produce collagen. The principle characteristics of this phaseare epithelialization, angiogenesis, granulation tissue formation andcollagen production. The proliferative phase typically occurs over days3-14. The third phase is the remodeling phase where matrix formationoccurs. The fibroblasts, epithelial cells, and endothelial cellscontinue to produce collagen and collagenase as well as matrixmetalloproteases (MMPs) for remodeling. Collagen crosslinking takesplace and the wound undergoes contraction. The remodeling phasetypically occurs from day 7 to one year.

Compounds and compositions described herein can be used for promotingwound healing (e.g., promoting or accelerating wound closure and/orwound healing, mitigating scar fibrosis of the tissue of and/or aroundthe wound, inhibiting apoptosis of cells surrounding or proximate to thewound). Thus, in certain embodiments, the present invention provides amethod for promoting wound healing in a subject, comprisingadministering to the subject a therapeutically effective amount of acompound (e.g., a CRM1 inhibitor), or pharmaceutically acceptable saltor composition thereof. The method need not achieve complete healing orclosure of the wound; it is sufficient for the method to promote anydegree of wound closure. In this respect, the method can be employedalone or as an adjunct to other methods for healing wounded tissue.

The compounds and compositions described herein can be used to treatwounds during the inflammatory (or early) phase, during theproliferative (or middle) wound healing phase, and/or during theremodeling (or late) wound healing phase.

In some embodiments, the subject in need of wound healing is a human oran animal, for example, a dog, a cat, a horse, a pig, or a rodent, suchas a mouse.

In some embodiments, the compounds and compositions described hereinuseful for wound healing are administered topically, for example,proximate to the wound site, or systemically.

More specifically, a therapeutically effective amount of a compound orcomposition described herein can be administered (optionally incombination with other agents) to the wound site by coating the wound orapplying a bandage, packing material, stitches, etc., that are coated ortreated with the compound or composition described herein. As such, thecompounds and compositions described herein can be formulated fortopical administration to treat surface wounds. Topical formulationsinclude those for delivery via the mouth (buccal) and to the skin suchthat a layer of skin (i.e., the epidermis, dermis, and/or subcutaneouslayer) is contacted with the compound or composition described herein.Topical delivery systems may be used to administer topical formulationsof the compounds and compositions described herein.

Alternatively, the compounds and compositions described herein can beadministered at or near the wound site by, for example, injection of asolution, injection of an extended release formulation, or introductionof a biodegradable implant comprising the compound or compositiondescribed herein.

The compounds and compositions described herein can be used to treatacute wounds or chronic wounds. A chronic wound results when the normalreparative process is interrupted. Chronic wounds can develop from acuteinjuries as a result of unrecognized persistent infections or inadequateprimary treatment. In most cases however, chronic lesions are the endstage of progressive tissue breakdown owing to venous, arterial, ormetabolic vascular disease, pressure sores, radiation damage, or tumors.

In chronic wounds, healing does not occur for a variety of reasons,including improper circulation in diabetic ulcers, significant necrosis,such as in burns, and infections. In these chronic wounds, viability orthe recovery phase is often the rate-limiting step. The cells are nolonger viable and, thus, initial recovery phase is prolonged byunfavorable wound bed environment.

Chronic wounds include, but are not limited to the following: chronicischemic skin lesions; scleroderma ulcers; arterial ulcers; diabeticfoot ulcers; pressure ulcers; venous ulcers; non-healing lower extremitywounds; ulcers due to inflammatory conditions; and/or long-standingwounds. Other examples of chronic wounds include chronic ulcers,diabetic wounds, wounds caused by diabetic neuropathy, venousinsufficiencies, and arterial insufficiencies, and pressure wounds andcold and warm burns. Yet other examples of chronic wounds includechronic ulcers, diabetic wounds, wounds caused by diabetic neuropathy,venous insufficiencies, arterial insufficiencies, and pressure wounds.

Acute wounds include, but are not limited to, post-surgical wounds,lacerations, hemorrhoids and fissures.

In a particular embodiment, the compounds and compositions describedherein can be used for diabetic wound healing or accelerating healing ofleg and foot ulcers secondary to diabetes or ischemia in a subject.

In one embodiment, the wound is a surface wound. In another embodiment,the wound is a surgical wound (e.g., abdominal or gastrointestinalsurgical wound). In a further embodiment, the wound is a burn. In yetanother embodiment, the wound is the result of radiation exposure.

The compounds and compositions described herein can also be used fordiabetic wound healing, gastrointestinal wound healing, or healing of anadhesion due, for example, to an operation.

The compounds and compositions described herein can also be used to healwounds that are secondary to another disease. For example, ininflammatory skin diseases, such as psoriasis and dermatitis, there arenumerous incidents of skin lesions that are secondary to the disease,and are caused by deep cracking of the skin, or scratching of the skin.The compounds and compositions described herein can be used to healwounds that are secondary to these diseases, for example, inflammatoryskin diseases, such as psoriasis and dermatitis.

In a further embodiment, the wound is an internal wound. In a specificaspect, the internal wound is a chronic wound. In another specificaspect, the wound is a vascular wound. In yet another specific aspect,the internal wound is an ulcer. Examples of internal wounds include, butare not limited to, fistulas and internal wounds associated withcosmetic surgery, internal indications, Crohn's disease, ulcerativecolitis, internal surgical sutures and skeletal fixation. Other examplesof internal wounds include, but are not limited to, fistulas andinternal wounds associated with cosmetic surgery, internal indications,internal surgical sutures and skeletal fixation.

Examples of wounds include, but are not limited to, abrasions,avulsions, blowing wounds (i.e., open pneumothorax), burn wounds,contusions, gunshot wounds, incised wounds, open wounds, penetratingwounds, perforating wounds, puncture wounds, séton wounds, stab wounds,surgical wounds, subcutaneous wounds, diabetic lesions, or tangentialwounds. Additional examples of wounds that can be treated by thecompounds and compositions described herein include acute conditions orwounds, such as thermal burns, chemical burns, radiation burns, burnscaused by excess exposure to ultraviolet radiation (e.g., sunburn);damage to bodily tissues, such as the perineum as a result of labor andchildbirth; injuries sustained during medical procedures, such asepisiotomies; trauma-induced injuries including cuts, incisions,excoriations; injuries sustained from accidents; post-surgical injuries,as well as chronic conditions, such as pressure sores, bedsores,conditions related to diabetes and poor circulation, and all types ofacne. In addition, the wound can include dermatitis, such as impetigo,intertrigo, folliculitis and eczema, wounds following dental surgery;periodontal disease; wounds following trauma; and tumor-associatedwounds. Yet other examples of wounds include animal bites, arterialdisease, insect stings and bites, bone infections, compromisedskin/muscle grafts, gangrene, skin tears or lacerations, skin aging,surgical incisions, including slow or non-healing surgical wounds,intracerebral hemorrhage, aneurysm, dermal asthenia, and post-operationinfections.

In preferred embodiments, the wound is selected from the groupconsisting of a burn wound, an incised wound, an open wound, a surgicalor post surgical wound, a diabetic lesion, a thermal burn, a chemicalburn, a radiation burn, a pressure sore, a bedsore, and a conditionrelated to diabetes or poor circulation. In more preferred embodiments,the wound is selected from the group consisting of an incised wound, anopen wound, a surgical or post surgical wound, a diabetic lesion, apressure sore, a bedsore, and a condition or wound related to diabetesor poor circulation.

In some embodiments, the wound is selected from the group consisting ofa non-radiation burn wound, an incised wound, an open wound, a surgicalor post-surgical wound, a diabetic lesion, a thermal burn, a chemicalburn, a pressure sore, a bedsore, and a condition related to diabetes orpoor circulation. In some embodiments, the wound is selected from thegroup consisting of an incised wound, an open wound, a surgical orpost-surgical wound, a diabetic lesion, a pressure sore, a bedsore, anda condition related to diabetes or poor circulation.

The present disclosure also relates to methods and compositions ofreducing scar formation during wound healing in a subject. The compoundsand compositions described herein can be administered directly to thewound or to cells proximate the wound at an amount effective to reducescar formation in and/or around the wound. Thus, in some embodiments, amethod of reducing scar formation during wound healing in a subject isprovided, the method comprising administering to the subject atherapeutically effective amount of a compound described herein (e.g., aCRM1 inhibitor), or a pharmaceutically acceptable salt thereof.

The wound can include any injury to any portion of the body of asubject. According to embodiments, methods are provided to ameliorate,reduce, or decrease the formation of scars in a subject that hassuffered a burn injury. According to preferred embodiments, methods areprovided to treat, reduce the occurrence of, or reduce the probabilityof developing hypertrophic scars in a subject that has suffered an acuteor chronic wound or injury.

Other Disorders

Compounds and compositions described herein may also be used to treatdisorders of abnormal tissue growth and fibrosis including dilativecardiomyopathy, hypertrophic cardiomyopathy, restrictive cardiomyopathy,pulmonary fibrosis, hepatic fibrosis, glomerulonephritis, and otherrenal disorders.

Combination Radiation Therapy

Compounds and compositions described herein are useful asradiosensitizers.

Therefore, compounds and compositions described herein can beadministered in combination with radiation therapy. Radiation therapy isthe medical use of high-energy radiation (e.g., X-rays, gamma rays,charged particles) to shrink tumors and kill malignant cells, and isgenerally used as part of cancer treatment. Radiation therapy killsmalignant cells by damaging their DNA.

Radiation therapy can be delivered to a patient in several ways. Forexample, radiation can be delivered from an external source, such as amachine outside the patient's body, as in external beam radiationtherapy. External beam radiation therapy for the treatment of canceruses a radiation source that is external to the patient, typicallyeither a radioisotope, such as ⁶⁰Co, ¹³⁷Cs, or a high energy x-raysource, such as a linear accelerator. The external source produces acollimated beam directed into the patient to the tumor site.External-source radiation therapy avoids some of the problems ofinternal-source radiation therapy, but it undesirably and necessarilyirradiates a significant volume of non-tumorous or healthy tissue in thepath of the radiation beam along with the tumorous tissue.

The adverse effect of irradiating of healthy tissue can be reduced,while maintaining a given dose of radiation in the tumorous tissue, byprojecting the external radiation beam into the patient at a variety of“gantry” angles with the beams converging on the tumor site. Theparticular volume elements of healthy tissue, along the path of theradiation beam, change, reducing the total dose to each such element ofhealthy tissue during the entire treatment.

The irradiation of healthy tissue also can be reduced by tightlycollimating the radiation beam to the general cross section of the tumortaken perpendicular to the axis of the radiation beam. Numerous systemsexist for producing such a circumferential collimation, some of whichuse multiple sliding shutters which, piecewise, can generate aradio-opaque mask of arbitrary outline.

For administration of external beam radiation, the amount can be atleast about 1 Gray (Gy) fractions at least once every other day to atreatment volume. In a particular embodiment, the radiation isadministered in at least about 2 Gray (Gy) fractions at least once perday to a treatment volume. In another particular embodiment, theradiation is administered in at least about 2 Gray (Gy) fractions atleast once per day to a treatment volume for five consecutive days perweek. In another particular embodiment, radiation is administered in 10Gy fractions every other day, three times per week to a treatmentvolume. In another particular embodiment, a total of at least about 20Gy is administered to a patient in need thereof. In another particularembodiment, at least about 30 Gy is administered to a patient in needthereof. In another particular embodiment, at least about 40 Gy isadministered to a patient in need thereof.

Typically, the patient receives external beam therapy four or five timesa week. An entire course of treatment usually lasts from one to sevenweeks depending on the type of cancer and the goal of treatment. Forexample, a patient can receive a dose of 2 Gy/day over 30 days.

Internal radiation therapy is localized radiation therapy, meaning theradiation source is placed at the site of the tumor or affected area.Internal radiation therapy can be delivered by placing a radiationsource inside or next to the area requiring treatment. Internalradiation therapy is also called brachytherapy. Brachytherapy includesintercavitary treatment and interstitial treatment. In intracavitarytreatment, containers that hold radioactive sources are put in or nearthe tumor. The sources are put into the body cavities. In interstitialtreatment, the radioactive sources alone are put into the tumor. Theseradioactive sources can stay in the patient permanently. Typically, theradioactive sources are removed from the patient after several days. Theradioactive sources are in containers.

There are a number of methods for administration of aradiopharmaceutical agent. For example, the radiopharmaceutical agentcan be administered by targeted delivery or by systemic delivery oftargeted radioactive conjugates, such as a radiolabeled antibody, aradiolabeled peptide and a liposome delivery system. In one particularembodiment of targeted delivery, the radiolabelled pharmaceutical agentcan be a radiolabelled antibody. See, for example, Ballangrud A. M., etal. Cancer Res., 2001; 61:2008-2014 and Goldenber, D. M. J. Nucl. Med.,2002; 43(5):693-713, the contents of which are incorporated by referenceherein.

In another particular embodiment of targeted delivery, theradiopharmaceutical agent can be administered in the form of liposomedelivery systems, such as small unilamellar vesicles, large unilamellarvesicles and multilamellar vesicles. Liposomes can be formed from avariety of phospholipids, such as cholesterol, stearylamine orphosphatidylcholines. See, for example, Emfietzoglou D, Kostarelos K,Sgouros G. An analytical dosimetry study for the use ofradionuclide-liposome conjugates in internal radiotherapy. J Nucl Med2001; 42:499-504, the contents of which are incorporated by referenceherein.

In yet another particular embodiment of targeted delivery, theradiolabeled pharmaceutical agent can be a radiolabeled peptide. See,for example, Weiner R E, Thakur M L. Radiolabeled peptides in thediagnosis and therapy of oncological diseases. Appl Radiat Isot 2002November; 57(5):749-63, the contents of which are incorporated byreference herein.

In addition to targeted delivery, bracytherapy can be used to deliverthe radiopharmaceutical agent to the target site. Brachytherapy is atechnique that puts the radiation sources as close as possible to thetumor site. Often the source is inserted directly into the tumor. Theradioactive sources can be in the form of wires, seeds or rods.Generally, cesium, iridium or iodine are used.

Systemic radiation therapy is another type of radiation therapy andinvolves the use of radioactive substances in the blood. Systemicradiation therapy is a form of targeted therapy. In systemic radiationtherapy, a patient typically ingests or receives an injection of aradioactive substance, such as radioactive iodine or a radioactivesubstance bound to a monoclonal antibody.

A “radiopharmaceutical agent,” as defined herein, refers to apharmaceutical agent which contains at least one radiation-emittingradioisotope. Radiopharmaceutical agents are routinely used in nuclearmedicine for the diagnosis and/or therapy of various diseases. Theradiolabelled pharmaceutical agent, for example, a radiolabelledantibody, contains a radioisotope (RI) which serves as the radiationsource. As contemplated herein, the term “radioisotope” includesmetallic and non-metallic radioisotopes. The radioisotope is chosenbased on the medical application of the radiolabeled pharmaceuticalagents. When the radioisotope is a metallic radioisotope, a chelator istypically employed to bind the metallic radioisotope to the rest of themolecule. When the radioisotope is a non-metallic radioisotope, thenon-metallic radioisotope is typically linked directly, or via a linker,to the rest of the molecule.

As used herein, a “metallic radioisotope” is any suitable metallicradioisotope useful in a therapeutic or diagnostic procedure in vivo orin vitro. Suitable metallic radioisotopes include, but are not limitedto: Actinium-225, Antimony-124, Antimony-125, Arsenic-74, Barium-103,Barium-140, Beryllium-7, Bismuth-206, Bismuth-207, Bismuth212,Bismuth213, Cadmium-109, Cadmium-115m, Calcium-45, Cerium-139,Cerium-141, Cerium-144, Cesium-137, Chromium-51, Cobalt-55, Cobalt-56,Cobalt-57, Cobalt-58, Cobalt-60, Cobalt-64, Copper-60, Copper-62,Copper-64, Copper-67, Erbium-169, Europium-152, Gallium-64, Gallium-67,Gallium-68, Gadolinium153, Gadolinium-157 Gold-195, Gold-199,Hafnium-175, Hafnium-175-181, Holmium-166, Indium-110, Indium-111,Iridium-192, Iron 55, Iron-59, Krypton85, Lead-203, Lead-210,Lutetium-177, Manganese-54, Mercury-197, Mercury203, Molybdenum-99,Neodymium-147, Neptunium-237, Nickel-63, Niobium95, Osmium-185+191,Palladium-103, Palladium-109, Platinum-195m, Praseodymium-143,Promethium-147, Promethium-149, Protactinium-233, Radium-226,Rhenium-186, Rhenium-188, Rubidium-86, Ruthenium-97, Ruthenium-103,Ruthenium-105, Ruthenium-106, Samarium-153, Scandium-44, Scandium-46,Scandium-47, Selenium-75, Silver-110m, Silver-111, Sodium-22,Strontium-85, Strontium-89, Strontium-90, Sulfur-35, Tantalum-182,Technetium-99m, Tellurium-125, Tellurium-132, Thallium-204, Thorium-228,Thorium-232, Thallium-170, Tin-113, Tin-114, Tin-117m, Titanium-44,Tungsten-185, Vanadium-48, Vanadium-49, Ytterbium-169, Yttrium-86,Yttrium-88, Yttrium-90, Yttrium-91, Zinc-65, Zirconium-89, andZirconium-95.

As used herein, a “non-metallic radioisotope” is any suitablenonmetallic radioisotope (non-metallic radioisotope) useful in atherapeutic or diagnostic procedure in vivo or in vitro. Suitablenon-metallic radioisotopes include, but are not limited to: Iodine-131,Iodine-125, Iodine-123, Phosphorus-32, Astatine-211, Fluorine-18,Carbon-11, Oxygen-15, Bromine-76, and Nitrogen-13.

Identifying the most appropriate isotope for radiotherapy requiresweighing a variety of factors. These include tumor uptake and retention,blood clearance, rate of radiation delivery, half-life and specificactivity of the radioisotope, and the feasibility of large-scaleproduction of the radioisotope in an economical fashion. The key pointfor a therapeutic radiopharmaceutical is to deliver the requisite amountof radiation dose to the tumor cells and to achieve a cytotoxic ortumoricidal effect while not causing unmanageable side-effects.

It is preferred that the physical half-life of the therapeuticradioisotope be similar to the biological half-life of theradiopharmaceutical at the tumor site. For example, if the half-life ofthe radioisotope is too short, much of the decay will have occurredbefore the radiopharmaceutical has reached maximum target/backgroundratio. On the other hand, too long a half-life could cause unnecessaryradiation dose to normal tissues. Ideally, the radioisotope should havea long enough half-life to attain a minimum dose rate and to irradiateall the cells during the most radiation sensitive phases of the cellcycle. In addition, the half-life of a radioisotope has to be longenough to allow adequate time for manufacturing, release, andtransportation.

Other practical considerations in selecting a radioisotope for a givenapplication in tumor therapy are availability and quality. The purityhas to be sufficient and reproducible, as trace amounts of impuritiescan affect the radiolabeling and radiochemical purity of theradiopharmaceutical.

The target receptor sites in tumors are typically limited in number. Assuch, it is preferred that the radioisotope have high specific activity.The specific activity depends primarily on the production method. Tracemetal contaminants must be minimized as they often compete with theradioisotope for the chelator and their metal complexes compete forreceptor binding with the radiolabeled chelated agent.

The type of radiation that is suitable for use in the methods of thepresent invention can vary. For example, radiation can beelectromagnetic or particulate in nature. Electromagnetic radiationuseful in the practice of this invention includes, but is not limitedto, x-rays and gamma rays. Particulate radiation useful in the practiceof this invention includes, but is not limited to, electron beams (betaparticles), protons beams, neutron beams, alpha particles, and negativepi mesons. The radiation can be delivered using conventionalradiological treatment apparatus and methods, and by intraoperative andstereotactic methods. Additional discussion regarding radiationtreatments suitable for use in the practice of this invention can befound throughout Steven A. Leibel et al., Textbook of Radiation Oncology(1998) (publ. W. B. Saunders Company), and particularly in Chapters 13and 14. Radiation can also be delivered by other methods such astargeted delivery, for example by radioactive “seeds,” or by systemicdelivery of targeted radioactive conjugates. J. Padawer et al., CombinedTreatment with Radioestradiol lucanthone in Mouse C3HBA MammaryAdenocarcinoma and with Estradiol lucanthone in an Estrogen Bioassay,Int. J. Radiat. Oncol. Biol. Phys. 7:347-357 (1981). Other radiationdelivery methods can be used in the practice of this invention.

For tumor therapy, both a and β-particle emitters have beeninvestigated. Alpha particles are particularly good cytotoxic agentsbecause they dissipate a large amount of energy within one or two celldiameters. The β-particle emitters have relatively long penetrationrange (2-12 mm in the tissue) depending on the energy level. Thelong-range penetration is particularly important for solid tumors thathave heterogeneous blood flow and/or receptor expression. The β-particleemitters yield a more homogeneous dose distribution even when they areheterogeneously distributed within the target tissue.

In a particular embodiment, therapeutically effective amounts of thecompounds and compositions described herein are administered incombination with a therapeutically effective amount of radiation therapyto treat cancer (e.g., lung cancer, such as non-small cell lung cancer).The amount of radiation necessary can be determined by one of skill inthe art based on known doses for a particular type of cancer. See, forexample, Cancer Medicine 5^(th) ed., Edited by R. C. Bast et al., July2000, BC Decker.

The above disclosure generally describes the present invention. A morecomplete understanding can be obtained by reference to the followingspecific Examples. These Examples are described solely for purposes ofillustration and are not intended to limit the scope of the invention.Changes in form and substitution of equivalents are contemplated ascircumstances may suggest or render expedient. Although specific termshave been employed herein, such terms are intended in a descriptivesense and not for purposes of limitation.

EXEMPLIFICATION

Abbreviations

aq. Aqueous

DMF N,N-Dimethylformamide

DMSO Dimethylsulfoxide

eq. equivalent(s)

Et Ethyl

EtOAc Ethyl acetate

g gram

h hour(s)

HPLC High performance liquid chromatography

LCMS Liquid Chromatography Mass Spectrometry

Me methyl

mg milligram(s)

min minute

mL milliliters

NMM N-methyl morpholine

NMR Nuclear magnetic resonance

Ph phenyl

THF Tetrahydrofuran

t_(R) Retention time

Throughout the following description of such processes it is to beunderstood that, where appropriate, suitable protecting groups will beadded to, and subsequently removed from, the various reactants andintermediates in a manner that will be readily understood by one skilledin the art of organic synthesis. Conventional procedures for using suchprotecting groups as well as examples of suitable protecting groups aredescribed, for example, in “Protective Groups in Organic Synthesis”, T.W. Green, P. G. M. Wuts, Wiley-Interscience, New York, (1999). It isalso to be understood that a transformation of a group or substituentinto another group or substituent by chemical manipulation can beconducted on any intermediate or final product on the synthetic pathtoward the final product, in which the possible type of transformationis limited only by inherent incompatibility of other functionalitiescarried by the molecule at that stage to the conditions or reagentsemployed in the transformation. Such inherent incompatibilities, andways to circumvent them by carrying out appropriate transformations andsynthetic steps in a suitable order, will be readily understood to theone skilled in the art of organic synthesis. Examples of transformationsare given below, and it is to be understood that the describedtransformations are not limited only to the generic groups orsubstituents for which the transformations are exemplified. Referencesand descriptions on other suitable transformations are given in“Comprehensive Organic Transformations—A Guide to Functional GroupPreparations” R. C. Larock, VHC Publishers, Inc. (1989). References anddescriptions of other suitable reactions are described in textbooks oforganic chemistry, for example, “Advanced Organic Chemistry”, March, 4thed. McGraw Hill (1992) or, “Organic Synthesis”, Smith, McGraw Hill,(1994). Techniques for purification of intermediates and final productsinclude for example, straight and reversed phase chromatography oncolumn or rotating plate, recrystallization, distillation andliquid-liquid or solid-liquid extraction, which will be readilyunderstood by the one skilled in the art. The definitions ofsubstituents and groups are as in formula I except where defineddifferently. The term “room temperature” and “ambient temperature” shallmean, unless otherwise specified, a temperature between 16 and 25° C.The term “reflux” shall mean, unless otherwise stated, in reference toan employed solvent a temperature at or above the boiling point of namedsolvent.

Synthetic Procedures Example 1. Preparation of(E)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-2-(4-(N-cyclopropylsulfamoyl)phenyl)acrylamide(Compound 100)

Compounds of the invention were prepared according to the methods shownin the following scheme. Intermediate 1 was prepared according toprocedures found in WO201405393.

A solution of(Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-2-bromoacrylamide(120 mg, 0.28 mmol), (4-(N-cyclopropylsulfammoyl)phenyl)boronic acid (89mg, 0.37 mmol), potassium acetate (69 mg, 0.7 mmol),[1,1′-bis(diphenylphosphino)ferrocene]palladium-(II) chloride (45 mg,0.06 mmol) in dioxane (7 mL) and water (1 mL) was degassed and thenheated at 80° C. for 1.5 h. The reaction mixture was poured into 10 mLof water and extracted with ethyl acetate (10 mL×3). The combinedorganic layers were washed with brine, dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure to give crude product, which waspurified prep-HPLC to afford(E)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-2-(4-cyanophenyl)acrylamide.¹H NMR (500 MHz, DMSO-d₆) δ 9.00 (s, 1H), 8.27 (s, 1H), 8.22 (s, 1H),8.04 (s, 2H), 7.90 (d, J=8 Hz, 2H), 7.61 (s, 1H), 7.47 (d, J=8 Hz, 2H),7.10 (s, 1H). LCMS: m/z 452.0 [M+H]⁺, t_(R)=1.93 min.The following examples were prepared in a similar fashion as Example 1using the indicated reagents.

Example 2. Preparation of(E)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-2-(4-(cyclopropylsulfonyl)phenyl)acrylamide(Compound 101)

¹H NMR (500 MHz, DMSO-d₆) δ 8.81 (s, 1H), 8.21 (s, 1H), 8.19 (d, J=3 Hz,3H), 7.92 (d, J=8 Hz, 2H), 7.62 (s, 1H), 7.55 (d, J=8 Hz, 2H), 7.34 (s,1H), 2.84-2.77 (m, 1H), 1.18-1.13 (m, 2H), 1.07-1.01 (m, 2H). LCMS: m/z530.7 [M+H]⁺, t_(R)=1.93 min.

Example 3. Preparation of(E)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-2-(3-(methylsulfonamido)phenyl)acrylamide(Compound 102)

¹H NMR (500 MHz, DMSO-d₆) δ 9.78 (s, 1H), 8.64 (s, 1H), 8.21 (s, 3H),8.12 (s, 1H), 7.59 (s, 1H), 7.44-7.36 (m, 1H), 7.28 (d, J=8 Hz, 1H),7.08 (s, 2H), 7.01 (d, J=8 Hz, 1H), 2.88 (s, 3H). LCMS: m/z 519.7[M+H]⁺, t_(R)=1.88 min.

Example 4. Preparation of(E)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-2-(4-(methylsulfonyl)phenyl)acrylamide(Compound 103)

¹H NMR (500 MHz, CD₃OD) δ 8.54 (s, 1H), 8.33-8.30 (m, 3H), 8.10 (d, J=8Hz, 2H), 8.03 (s, 1H), 7.66 (d, J=8 Hz, 2H), 3.20 (s, 3H). LCMS: m/z505.0 [M+H]⁺, t_(R)=1.67 min.

Example 5. Preparation of(E)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-2-(4-(N,N-dimethylsulfamoyl)phenyl)acrylamide(Compound 104)

¹H NMR (500 MHz, DMSO-d₆) δ 8.96 (s, 1H), 8.55 (s, 2H), 8.29 (s, 1H),8.05 (s, 1H), 7.95 (s, 1H), 7.90-7.80 (m, 5H), 2.65 (s, 6H). LCMS: m/z534.1 [M+H]⁺, t_(R)=1.92 min.

Compounds 105-128 were synthesized from Intermediate 1, utilizing theappropriate boronates/boronic acids and the reagents shown in Examples1-5:

(E)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-2-(4-(4,4-difluoropiperidin-1-ylsulfonyl)phenyl)acrylamide(Compound 105)

¹H NMR (500 MHz, DMSO-d₆) δ 8.81 (s, 1H), 8.21 (s, 2H), 8.18 (s, 2H),7.79 (d, J=8 Hz, 2H), 7.65 (s, 1H), 7.55 (d, J=8 Hz, 2H), 7.25 (s, 1H),3.14-3.09 (m, 4H), 2.13-2.00 (m, 4H).

LCMS: m/z 610.1 [M+H]⁺, t_(R)=1.77 min.

(E)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-2-(4-(4-(trifluoromethyl)piperidin-1-ylsulfonyl)phenyl)acrylamide(Compound 106)

¹H NMR (500 MHz, DMSO-d₆) δ 8.79 (s, 1H), 8.22-8.17 (m, 4H), 7.77 (d,J=8 Hz, 2H), 7.68 (s, 1H), 7.56 (d, J=8 Hz, 2H), 7.20 (s, 1H), 3.79-3.71(m, 2H), 2.38-2.24 (m, 3H), 1.88-1.78 (m, 2H), 1.55-1.39 (m, 2H). LCMS:m/z 642.2 [M+H]⁺, t_(R)=2.04 min.

(E)-2-(4-(azetidin-1-ylsulfonyl)phenyl)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylamide(Compound 107)

¹H NMR (500 MHz, CD₃OD) δ 8.29 (s, 1H), 8.23 (s, 2H), 8.16 (s, 1H), 7.91(s, 1H), 7.86-7.83 (m, 2H), 7.58-7.54 (m, 2H), 3.74-3.68 (m, 4H),2.00-1.91 (m, 2H). LCMS: m/z 546.1 [M+H]⁺, t_(R)=1.91 min.

(E)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-2-(4-(morpholinosulfonyl)phenyl)acrylamide(Compound 108)

¹H NMR (500 MHz, DMSO-d₆) δ 8.82 (s, 1H), 8.26-8.15 (m, 4H), 7.75 (d,J=8 Hz, 2H), 7.67 (s, 1H), 7.55 (d, J=8 Hz, 2H), 7.19 (s, 1H), 3.66-3.61(m, 4H), 2.95-2.88 (m, 4H). LCMS: m/z 576.1 [M+H]⁺, t_(R)=1.72 min.

(E)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-2-(4-(piperidin-1-ylsulfonyl)phenyl)acrylamide(Compound 109)

¹H NMR (500 MHz, DMSO-d₆) δ 8.77 (s, 1H), 8.22-8.17 (m, 4H), 7.74 (d,J=8 Hz, 2H), 7.67 (s, 1H), 7.53 (d, J=8 Hz, 2H), 7.25 (s, 1H), 2.96-2.86(m, 4H), 1.59-1.48 (m, 4H), 1.37-1.28 (m, 2H). LCMS: m/z 574.1 [M+H]⁺,t_(R)=1.75 min.

Synthesis of(E)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-2-(4-(3-fluoroazetidin-1-ylsulfonyl)phenyl)acrylamide(Compound 110)

¹H NMR (500 MHz, DMSO-d₆) δ 8.80 (s, 1H), 8.24-8.15 (m, 4H), 7.87 (d,J=8 Hz, 2H), 7.67 (s, 1H), 7.60 (d, J=8 Hz, 2H), 7.20 (s, 1H), 5.24-5.07(m, 1H), 4.13-4.01 (m, 2H), 3.85-3.73 (m, 2H). LCMS: m/z 564.1 [M+H]⁺,t_(R)=1.91 min.

(E)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-2-(4-(3,3-difluoroazetidin-1-ylsulfonyl)phenyl)acrylamide(Compound 111)

¹H NMR (500 MHz, DMSO-d₆) δ 8.81 (s, 1H), 8.26-8.14 (m, 4H), 7.93 (d,J=8 Hz, 2H), 7.66 (s, 1H), 7.62 (d, J=8 Hz, 2H), 7.18 (s, 1H), 4.31-4.22(m, 4H). LCMS: m/z 582.1 [M+H]⁺, t_(R)=1.95 min.

(E)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-2-(4-(pyrrolidin-1-ylsulfonyl)phenyl)acrylamide(Compound 112)

¹H NMR (500 MHz, DMSO-d₆) δ 8.74 (s, 1H), 8.22 (s, 1H), 8.21 (s, 2H),8.18 (s, 1H), 7.82 (d, J=8 Hz, 2H), 7.65 (s, 1H), 7.52 (d, J=8 Hz, 2H),7.26 (s, 1H), 3.17-3.11 (m, 4H), 1.65-1.59 (m, 4H). LCMS: m/z 560.1[M+H]⁺, t_(R)=2.00 min.

(E)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-2-(4-(3,3-difluoropyrrolidin-1-ylsulfonyl)phenyl)acrylamide(Compound 113)

¹H NMR (500 MHz, DMSO-d₆) δ 8.77 (s, 1H), 8.21 (s, 2H), 8.18 (s, 2H),7.87 (d, J=8 Hz, 2H), 7.67 (s, 1H), 7.56 (d, J=8 Hz, 2H), 7.17 (s, 1H),3.60-3.53 (m, 2H), 3.41-3.37 (m, 2H), 2.36-2.29 (m, 2H). LCMS: m/z 596.1[M+H]⁺, t_(R)=2.01 min.

(E)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-2-(4-(4-fluoropiperidin-1-ylsulfonyl)phenyl)acrylamide(Compound 114)

¹H NMR (500 MHz, DMSO-d₆) δ 8.78 (s, 1H), 8.22-8.17 (m, 4H), 7.77 (d,J=8 Hz, 2H), 7.66 (s, 1H), 7.54 (d, J=8 Hz, 2H), 7.27 (s, 1H), 4.80-4.63(m, 1H), 3.09-2.93 (m, 4H), 1.97-1.73 (m, 4H). LCMS: m/z 592.2 [M+H]⁺,t_(R)=1.98 min.

(E)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-2-(4-(4-methylpiperazin-1-ylsulfonyl)phenyl)acrylamide(Compound 115)

¹H NMR (500 MHz, DMSO-d₆) δ 8.78 (s, 1H), 8.21 (s, 2H), 8.18 (s, 2H),7.74 (d, J=8 Hz, 2H), 7.65 (s, 1H), 7.53 (d, J=8 Hz, 2H), 7.22 (s, 1H),2.95-2.87 (m, 4H), 2.38-2.32 (m, 4H), 2.12 (s, 3H). LCMS: m/z 589.2[M+H]⁺, t_(R)=1.93 min.

(E)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-2-(4-(2,2-dimethylmorpholinosulfonyl)phenyl)acrylamide(Compound 116)

¹H NMR (500 MHz, DMSO-d₆) δ 8.79 (s, 1H), 8.22 (s, 1H), 8.20 (s, 1H),8.17 (s, 2H), 7.73 (d, J=8 Hz, 2H), 7.67 (s, 1H), 7.54 (d, J=8 Hz, 2H),7.19 (s, 1H), 3.70-3.64 (m, 2H), 2.89-2.83 (m, 2H), 2.70 (s, 2H), 1.16(s, 6H). LCMS: m/z 604.2 [M+H]⁺, t_(R)=1.98 min.

(R,E)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-2-(4-(3-fluoropyrrolidin-1-ylsulfonyl)phenyl)acrylamide(Compound 117)

¹H NMR (500 MHz, DMSO-d₆) δ 8.67 (s, 1H), 8.23-8.21 (m, 3H), 8.18 (s,1H), 7.84 (d, J=8 Hz, 2H), 7.65 (s, 1H), 7.54 (d, J=8 Hz, 2H), 7.18 (s,1H), 5.26-5.10 (m, 1H), 3.54-3.21 (m, 4H), 2.05-1.94 (m, 2H). LCMS: m/z578.1 [M+H]⁺, t_(R)=1.97 min.

(E)-2-(4-(1,4-oxazepan-4-ylsulfonyl)phenyl)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylamide(Compound 118)

¹H NMR (500 MHz, DMSO-d₆) δ 8.76 (s, 1H), 8.23-8.16 (m, 4H), 7.81 (d,J=8 Hz, 2H), 7.65 (s, 1H), 7.51 (d, J=8 Hz, 2H), 7.25 (s, 1H), 3.70-3.62(m, 4H), 3.34-3.29 (m, 4H), 1.87-1.76 (m, 2H). LCMS: m/z 590.2 [M+H]⁺,t_(R)=2.11 min.

(E)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-2-(3-(morpholinosulfonyl)phenyl)acrylamide(Compound 119)

¹H NMR (500 MHz, DMSO-d₆) δ 8.98 (s, 1H), 8.28 (s, 1H), 8.18 (s, 1H),8.07 (s, 2H), 7.80-7.66 (m, 3H), 7.63 (s, 1H), 7.49 (s, 1H), 7.23 (s,1H), 3.40-3.36 (m, 4H), 2.73-2.66 (m, 4H). LCMS: m/z 576.2 [M+H]⁺,t_(R)=1.95 min.

(E)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-2-(3-(4-fluoropiperidin-1-ylsulfonyl)phenyl)acrylamide(Compound 120)

¹H NMR (500 MHz, DMSO-d₆) δ 8.95 (s, 1H), 8.26 (s, 1H), 8.19 (s, 1H),8.08 (s, 2H), 7.81-7.65 (m, 3H), 7.60 (s, 1H), 7.52 (s, 1H), 7.23 (s,1H), 4.47-4.30 (m, 1H), 2.99-2.91 (m, 2H), 2.77-2.68 (m, 2H), 1.80-1.54(m, 4H). LCMS: m/z 592.1 [M+H]⁺, t_(R)=2.01 min.

(E)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-2-(3-(3,3-difluoroazetidin-1-ylsulfonyl)phenyl)acrylamide(Compound 121)

¹H NMR (500 MHz, DMSO-d₆) δ 8.94 (s, 1H), 8.27 (s, 1H), 8.20 (s, 1H),8.10 (s, 2H), 7.94 (d, J=8 Hz, 1H), 7.80-7.70 (m, 3H), 7.63 (s, 1H),7.25 (s, 1H), 4.16 (t, J=13 Hz, 4H). LCMS: m/z 582.1 [M+H]⁺, t_(R)=1.98min.

(E)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-2-(3-(4,4-difluoropiperidin-1-ylsulfonyl)phenyl)acrylamide(Compound 122)

¹H NMR (500 MHz, DMSO-d₆) δ 8.98 (s, 1H), 8.28 (s, 1H), 8.20 (s, 1H),8.06 (s, 2H), 7.81 (d, J=8 Hz, 1H), 7.75 (t, J=8 Hz, 1H), 7.69 (d, J=8Hz, 1H), 7.61 (s, 1H), 7.55 (s, 1H), 7.24 (s, 1H), 2.97-2.89 (m, 4H),1.93-1.82 (m, 4H). LCMS: m/z 610.1 [M+H]⁺, t_(R)=2.00 min.

(E)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-2-(3-(3-fluoroazetidin-1-ylsulfonyl)phenyl)acrylamide(Compound 123)

¹H NMR (500 MHz, DMSO-d₆) δ 8.95 (s, 1H), 8.27 (s, 1H), 8.19 (s, 1H),8.09 (s, 2H), 7.88 (d, J=8 Hz, 1H), 7.77 (t, J=8 Hz, 1H), 7.71 (d, J=8Hz, 1H), 7.67 (s, 1H), 7.63 (s, 1H), 7.24 (s, 1H), 5.10-4.93 (m, 1H),4.02-3.92 (m, 2H), 3.71-3.60 (m, 2H). LCMS: m/z 564.1 [M+H]⁺, t_(R)=1.97min.

(E)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-2-(3-(4-methylpiperazin-1-ylsulfonyl)phenyl)acrylamide(Compound 124)

¹H NMR (500 MHz, CDCl₃) δ 8.26 (s, 1H), 8.10 (s, 2H), 8.07 (s, 1H), 7.86(d, J=8 Hz, 1H), 7.78 (s, 1H), 7.70 (t, J=8 Hz, 1H), 7.61 (t, J=4 Hz,2H), 5.61 (s, 1H), 5.39 (s, 1H), 2.93-2.72 (m, 4H), 2.29-2.13 (m, 4H),1.99 (s, 3H). LCMS: m/z 589.2 [M+H]⁺, t_(R)=1.99 min.

(E)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-2-(3-(pyrrolidin-1-ylsulfonyl)phenyl)acrylamide(Compound 125)

¹H NMR (500 MHz, DMSO-d₆) δ 8.93 (s, 1H), 8.24 (s, 1H), 8.23 (s, 1H),8.09 (s, 2H), 7.82 (d, J=8 Hz, 1H), 7.72 (t, J=8 Hz, 1H), 7.66 (d, J=8Hz, 1H), 7.62 (s, 1H), 7.57 (s, 1H), 7.25 (s, 1H), 2.98 (t, J=7 Hz, 4H),1.36 (t, J=7 Hz, 4H). LCMS: m/z 560.2 [M+H]⁺, t_(R)=1.80 min.

(E)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-2-(3-(4-(trifluoromethyl)piperidin-1-ylsulfonyl)phenyl)acrylamide(Compound 126)

¹H NMR (500 MHz, DMSO-d₆) δ 8.96 (s, 1H), 8.27 (s, 1H), 8.23 (s, 1H),8.09 (s, 2H), 7.77 (d, J=5 Hz, 2H), 7.73-7.68 (m, 1H), 7.63 (s, 1H),7.50 (s, 1H), 7.19 (s, 1H), 3.60 (d, J=11 Hz, 2H), 1.97-1.89 (m, 2H),1.57-1.50 (m, 2H), 1.39-1.30 (m, 3H). LCMS: m/z 642.1 [M+H]⁺, t_(R)=2.10min.

(E)-2-(3-(azetidin-1-ylsulfonyl)phenyl)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylamide(Compound 127)

¹H NMR (500 MHz, DMSO-d₆) δ 8.98 (s, 1H), 8.28 (s, 1H), 8.22 (s, 1H),8.10 (s, 2H), 7.83 (d, J=8 Hz, 1H), 7.78 (t, J=8 Hz, 1H), 7.71 (d, J=8Hz, 1H), 7.64 (s, 1H), 7.58 (s, 1H), 7.28 (s, 1H), 3.53 (t, J=8 Hz, 4H),1.71-1.60 (m, 2H). LCMS: m/z 546.0 [M+H]⁺, t_(R)=1.75 min.

(E)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-2-(3-(3,3-difluoropyrrolidin-1-ylsulfonyl)phenyl)acrylamide(Compound 128)

¹H NMR (500 MHz, DMSO-d₆) δ 8.94 (s, 1H), 8.28 (s, 1H), 8.20 (s, 1H),8.08 (s, 2H), 7.87 (d, J=8 Hz, 1H), 7.75 (t, J=8 Hz, 1H), 7.71-7.66 (m,2H), 7.64 (s, 1H), 7.17 (s, 1H), 3.43 (t, J=13 Hz, 2H), 3.27 (t, J=7 Hz,2H), 2.20-2.06 (m, 2H). LCMS: m/z 596.1 [M+H]⁺, t_(R)=1.77 min.

Example 6. Assays

Certain compounds of the invention were tested in various assays.

Inhibition of Nuclear Export—Rev-GFP Assay

The inhibition of CRM1 mediated nuclear export by compounds of theinvention can be determined in a RevGFP assay. Rev is a protein fromhuman immunodeficiency virus type 1 (HIV-1) and contains a nuclearexport signal (NES) in its C-terminal domain and a nuclear localizationsignal (NLS) in its N-terminal domain. Nuclear export of Rev protein isdependent on the classical NES/CRM1 pathway (Neville et al, 1997, Kau etal, 2003). Nuclear and nucleolar accumulation of Rev is observed incells treated with specific inhibitors of CRM1, such as LMB (Kau et al,2003).

In this assay, U2OS-RevGFP cells are seeded onto clear-bottom, black,384-well plates the day before the experiment. Compounds are seriallydiluted 1:2 starting from 40 μM in a separate 384-well plate in DMEM,and then transferred onto cells. Cells are incubated with compound forapproximately 1 hour before fixation with 3.7% formaldehyde and nucleistaining with Hoechst 33258. The amount of GFP in cell nuclei ismeasured and compound IC₅₀s are determined (Kau et al, 2003).

MTT Cell Proliferation Assay

The MTT cell proliferation assay was used to study the cytotoxicproperties of the compounds. The assay was performed according to themethod described by Roche Molecular Biochemicals, with minormodifications. The assay is based on the cleavage of the tetrazoliumsalt, MTT, in the presence of an electron-coupling reagent. Thewater-insoluble formazan salt produced must be solubilized in anadditional step. Cells grown in a 96-well tissue culture plate wereincubated with the MTT solution for approximately 4 hours. After thisincubation period, a water-insoluble formazan dye formed. Aftersolubilization, the formazan dye was quantitated using a scanningmulti-well spectrophotometer (ELISA reader). The absorbance revealeddirectly correlates to the cell number. The cells were seeded at5,000-10,000 cells in each well of 96-well plate in 100 μL of freshculture medium and were allowed to attach overnight. The stock solutionsof the compounds were diluted in 100 μL cell culture medium to obtaineight concentrations of each test compound, ranging from 1 nM to 30 μM.After incubation for approximately 64-72 hours, 20 μL of CellTiter 96Aqueous One Solution Reagent (Promega, G358B) was added to each well andthe plate was returned to the incubator (37° C.; 5% CO₂) until anabsolute OD of 1.5 was reached for the control cells. All opticaldensities were measured at 490 nm using a Vmax Kinetic Microplate Reader(Molecular Devices). In most cases, the assay was performed in duplicateand the results were presented as a mean percent inhibition to thenegative control±SE. The following formula was used to calculate thepercent of inhibition: Inhibition (%)=(1−(OD_(o)/OD))×100.

The compounds were tested against Z138, MM1S and 3T3 cells. The Z138cell line is a mature B-cell acute lymphoblastic leukemia cell linederived from a patient with chronic lumphocytic leukemia. The MM1S cellline was established from the peripheral blood of a human multiplemyeloma patient. 3T3 cells are standard fibroblast cells; they wereoriginally isolated from Swiss mouse embryo tissue.

The results of the MTT assay are reported in Table 1.

TABLE 1 Assay Results for Exemplary Compounds (A = <100 nM; B = 100 nMto <5 μM; C = 5 μM to 30 μM; D = >30 μM; NT = Not tested). Cmpd. MTT MTTMTT No. Structure (MM1S) (Z138) (3T3) Name 100

A A D (E)-3-(3-(3,5- bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-2-(4-(N- cyclopropylsulfamoyl)phenyl) acrylamide101

A A A (E)-3-(3-(3,5- bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-2-(4- (cyclopropylsulfonyl)phenyl) acrylamide 102

B B D (E)-3-(3-(3,5- bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-2-(3- (methylsulfonamido)phenyl) acrylamide 103

A B D (E)-3-(3-(3,5- bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-2-(4- (methylsulfonyl)phenyl) acrylamide 104

B B D (E)-3-(3-(3,5- bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-2-(4- (N,N- dimethylsulfamoyl)phenyl) acrylamide105

A A B (E)-3-(3-(3,5- bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-2-(4- ((4,4-difluoropiperidin-1-yl)sulfonyl)phenyl)acrylamide 106

B B D (E)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-trlazol-1-yl)-2-(4-((4- (trifluoromethyl)piperidin-1-yl)sulfonyl)phenyl)acrylamide 107

A A B (E)-2-(4-(azetidin-1-ylsulfonyl)phenyl)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H- 1,2,4-triazol-1-yl)acrylamide108

A B B (E)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-2-(4- (morpholinosulfonyl)phenyl)acrylamide 109

B B B (E)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-2-(4-(piperidin-1- ylsulfonyl)phenyl)acrylamide110

A A B (E)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-2-(4-((3- fluoroazetidin-1-yl)sulfonyl)phenyl)acrylamide 111

A A B (E)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-2-(4-((3,3- difluoroazetidin-1-yl)sulfonyl)phenyl)acrylamide 112

A A B (E)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-2-(4-(pyrrolidin-1- ylsulfonyl)phenyl)acrylamide113

A A A (E)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-2-(4-((3,3- difluoropyrrolidin-1-yl)sulfonyl)phenyl)acrylamide 114

A A A (E)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-2-(4-((4- fluoropiperidin-1-yl)sulfonyl)phenyl)acrylamide 115

B B B (E)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-2-(4-((4- methylpiperazin-1-yl)sulfonyl)phenyl)acrylamide 116

B B B (E)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-2-(4-((2,2- dimethylmorpholino)sulfonyl)phenyl)acrylamide 117

A A B (R, E)-3-(3-(3,5- bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-2-(4-((3-fluoropyrrolidin-1- yl)sulfonyl)phenyl)acrylamide118

A A B (E)-2-(4-((1,4-oxazepan-4- yl)sulfonyl)phenyl)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4- triazol-1-yl)acrylamide 119

B B D (E)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-2-(3- (morpholinosulfonyl)phenyl)acrylamide 120

B B D (E)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-2-(3-((4- fluoropiperidin-1-yl)sulfonyl)phenyl)acrylamide 121

B B D (E)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-2-(3-((3,3- difluoroazetidin-1-yl)sulfonyl)phenyl)acrylamide 122

B B D (E)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-2-(3-((4,4- difluoropiperidin-1-yl)sulfonyl)phenyl)acrylamide 123

B B D (E)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-2-(3-((3- fluoroazetidin-1-yl)sulfonyl)phenyl)acrylamide 124

B B D (E)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-2-(3-((4- methylpiperazin-1-yl)sulfonyl)phenyl)acrylamide 125

B B D (E)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-2-(3-(pyrrolidin-1- ylsulfonyl)phenyl)acrylamide126

C B D (E)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-2-(3-((4- (trifluoromethyl)piperidin-1-yl)sulfonyl)phenyl)acrylamide 127

B B B (E)-2-(3-(azetidin-1-ylsulfonyl)phenyl)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H- 1,2,4-triazol-1-yl)acrylamide128

D B B (E)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-2-(3-((3,3- difluoropyrrolidin-1-yl)sulfonyl)phenyl)acrylamide

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The teachings of all patents, published applications and referencescited herein are incorporated by reference in their entirety.

While this invention has been particularly shown and described withreferences to example embodiments thereof, it will be understood bythose skilled in the art that various changes in form and details may bemade therein without departing from the scope of the inventionencompassed by the appended claims.

What is claimed is:
 1. A compound represented by the followingstructural formula:

or a pharmaceutically acceptable salt thereof, wherein: each R¹, ifpresent, is independently selected from —CF₃, —CN, halo, —OH, C₁-C₃alkyl, C₃-C₆ cycloalkyl, 3-18-membered heterocyclyl, —NH₂, halo-C₁-C₃alkyl, —NO₂, —NH(C₁-C₃ alkyl), —C(O)O—(C₁-C₆ alkyl), —N(C₁-C₃alkyl)(C₁-C₃ alkyl), —C(O)OH, —C(O)—(C₁-C₃ alkyl), —O—(C₁-C₃ alkyl),—O—(C₁-C₃ haloalkyl), and —S—(C₁-C₃ alkyl); R² is a 6-18-membered arylsubstituted with one or more substituents, wherein at least onesubstituent is —S(O)₁₋₂—R⁸ or N(H)S(O)₁₋₂—R⁸; R^(b) is selected from—C(O)—N(R⁵)(R⁶), —C(O)—O—R³, —C(O)—N(R⁷)—N(R⁵)(R⁶),—C(O)—N(R⁷)—N(R⁷)—C(O)—R⁴ and —C(O)—N(R⁷)—N(R⁷)—S(O)₁₋₂—R⁴; wherein: R³is selected from hydrogen, —C₁-C₄ alkyl, —C₂-C₄ alkenyl, —C₂-C₄ alkynyl,C₃-C₁₈s carbocyclyl, C₆-C₁₈ aryl, 3-18-member heterocyclyl and5-18-member heteroaryl; R⁴ is selected from —N(H)(C₃-C₆ cycloalkyl),—N(C₁-C₄ alkyl)(C₃-C₆ cycloalkyl), —C₁-C₆ alkyl, —(C₀-C₄alkylene)-C₃-C₁₈ carbocyclyl, —(C₀-C₄ alkylene)-3-18-memberheterocyclyl, —(C₀-C₄ alkylene)-C₆-C₁₈ aryl, and —(C₀-C₄alkylene)-5-18-member heteroaryl; R⁵ and R⁶ are each independentlyselected from hydrogen, —C₁-C₄ alkyl, —C₂-C₄ alkenyl, —C₂-C₄ alkynyl,C₃-C₁₈ carbocyclyl, C₆-C₁₈ aryl, 3-18-member heterocyclyl and5-18-member heteroaryl; or R⁵ and R⁶ are taken together with thenitrogen atom to which they are commonly attached to form a 3-18-memberheterocyclyl or 5-18-member heteroaryl; and each R⁷ is independentlyhydrogen or —C₁-C₄ alkyl; R⁸ is selected from —N(R⁹)—R¹⁰, (C₁-C₄)alkyl,(C₁-C₄)haloalkyl, —(C₀-C₄ alkylene) C₃-C₁₈ carbocyclyl, and —(C₀-C₄alkylene)-3-18-member heterocyclyl; R⁹ is hydrogen or —C₁-C₄ alkyl; R¹⁰is selected from —(C₁-C₄)alkyl, —(C₁-C₄)haloalkyl, —(C₀-C₄alkylene)-C₃-C₁₈ carbocyclyl and —(C₀-C₄ alkylene)-3-18-memberheterocyclyl; or R⁹ and R¹⁰ are taken together with the nitrogen atom towhich they are commonly attached to form a 4-7-membered heterocyclyl; nis 0, 1, 2, 3, 4 or 5, wherein: unless otherwise designated, each alkyl,alkenyl, alkynyl, alkylene, carbocyclyl, aryl, cycloalkyl, heterocyclyland heteroaryl is optionally and independently substituted.
 2. Thecompound of claim 1, wherein R^(b) is selected from C(O)—NH₂, —C(O)—OH,—C(O)—N(R⁷)—N(R⁵)(R⁶), —C(O)—N(R⁷)—N(R⁷)—C(O)—R⁴ and—C(O)—N(R⁷)—N(R⁷)—S(O)₁₋₂—R⁴.
 3. The compound of claim 2, wherein R^(b)is —C(O)NH₂.
 4. The compound of claim 1, wherein R² is phenyl.
 5. Thecompound of claim 1, wherein the at least one substituent of R² is—S(O)₁₋₂—R⁸.
 6. The compound of claim 1, wherein the at least onesubstituent of R² is —N(H)S(O)₁₋₂—R⁸.
 7. The compound of claim 5,wherein R⁸ is —N(Me)-Me or —N(H)-cyclopropyl.
 8. The compound of claim1, wherein R⁸ is —(C₁-C₄)alkyl, —(C₁-C₄)haloalkyl, —(C₀-C₄alkylene-C₃-C₁₈ carbocyclyl, or —(C₀-C₄ alkylene)-3-18-memberheterocyclyl wherein each alkyl, carbocyclyl and heterocyclyl isoptionally substituted.
 9. The compound of claim 8, wherein R⁸ isoptionally substituted cyclopropyl.
 10. The compound of claim 1, whereinR⁸ is an optionally substituted 3-12-membered heterocyclyl.
 11. Thecompound of claim 1, wherein R⁸ is substituted with 1, 2 or 3substituents independently selected from halo, hydroxyl,halo(C₁-C₃)alkyl, (C₁-C₃)alkyl and (C₁-C₃)alkoxy.
 12. The compound claim10, wherein R⁸ is selected from:


13. The compound of claim 1, wherein n is 1 or 2 and each R¹ isindependently selected from halo, (C₁-C₄)alkyl, (C₁-C₄)haloalkyl and—O—(C₁-C₄)alkyl.
 14. The compound of claim 1, wherein the compound isrepresented by the following structural formula:

or a pharmaceutically acceptable salt thereof, wherein: R^(1a) andR^(1b) are independently selected from —CF₃, —CN, halo, —OH,(C₁-C₃)alkyl, (C₃-C₆)cycloalkyl, 3-12-membered heterocyclyl,halo-(C₁-C₃)alkyl, —NH₂, —NO₂, —NH(C₁-C₃ alkyl), —N(C₁-C₃ alkyl)(C₁-C₃alkyl), —C(O)OH, —C(O)O—(C₁-C₆ alkyl), —C(O)—(C₁-C₃ alkyl), —O—(C₁-C₃alkyl), —O—(C₁-C₃ haloalkyl), and —S—(C₁-C₃ alkyl); and m is 0 or
 1. 15.The compound of claim 14, wherein R^(1a) is halo or (C₁-C₃)haloalkyl.16. The compound of claim 14, wherein R^(1b) is (C₁-C₃)haloalkyl or—O(C₁-C₃)alkyl.
 17. The compound of claim 14, wherein R^(1a) is —CF₃ andR^(1b) is —CF₃.
 18. A pharmaceutically composition comprising a compoundof claim 1, or a pharmaceutically acceptable salt thereof, and apharmaceutically acceptable carrier.
 19. A method for treating adisorder associated with CRM1 activity, the method comprisingadministering to a subject in need thereof a therapeutically effectiveamount of a compound of claim 1 or a pharmaceutically acceptable saltthereof.
 20. A compound represented by any one of the structuralformulas selected from:

or a pharmaceutically acceptable salt thereof.